Combination therapies with farnesoid x receptor (fxr) modulators

ABSTRACT

Described herein are methods of treating a metabolic disorder in an individual in need thereof, comprising co-administering to the individual a therapeutically effective amount of an FXR modulator, and at least one second agent that is an CCR2/CCR5 antagonist, ASK1 inhibitor, DPP-IV inhibitor, caspase protease inhibitor, SGLT2 inhibitor, acetyl-CoA carboxylase (ACC) inhibitor, diacylglycerol acyltransferase-1 inhibitor, sodium-bile acid cotransporter-inhibitor, TLR-4 antagonist, PPAR alpha/delta agonist, or GLP-1 agonist, or a combination thereof.

CROSS-REFERENCE

This application is a national stage of PCT International ApplicationNo. PCT/US2017/034564, filed May 25, 2017, which claims the benefit ofand priority to U.S. provisional application No. 62/341,482, filed May25, 2016, and U.S. provisional application No. 62/341,487, filed May 25,2016. The entire contents of each of which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

There is a need for new therapy regimens for the treatment of metabolicdisorders.

BACKGROUND OF THE INVENTION

Metabolic disease including obesity, diabetes, hypertension, andcardiovascular disease, are diseases driven by both mulitfactorialgenetics (thrifty genotypes) as well as lifestyle habits, and are nowreaching epidemic proportions in developed nations. It is believed thatincreasingly high caloric diets combined with sedentary life styles aremajor contributors to the growing incidence of these diseases.Importantly hyperlipidemia is associated with many types of metabolicdisease, and statistics from the American Heart Association indicatethat approximately half of the adult population in the United States hasplasma cholesterol levels that put individuals at risk for thedevelopment of cardiovascular disease (American Heart Association, Heartdisease and stroke statistics—2005 update; 2005:1-59). Furthermore, theThird Report of the National Cholesterol Education Program Expert Panelon Detection, Evaluation, and Treatment of High Blood Cholesterol inAdults (Adult Treatment Panel III; ATPIII, National CholesterolEducation Program 2001) has identified elevated triglyceride levels asan independent risk factor for the development of cardiovasculardisease. Approximately one third of the adult population in the UnitedStates that have elevated cholesterol levels also have increasedtriglycerides. The elevation in plasma triglycerides has now beenrecognized as an early and dominant dyslipidemic symptom in patientswith obesity, metabolic syndrome and diabetes and has been suggested toplay a causative role in the development of insulin resistance and typeII diabetes (Hegarty et al., Acta Physiol Scand 2003; 178(4):373-83;Shulman, J Clin Invest 2000; 106(2):171-6).

Current standard of care for hyperlipidemia focuses on lowering lowdensity lipoprotein cholesterol (LDL) using the statin class ofhydroxymethy-glutaryl-CoA reductase inhibitors (National CholesterolEducation Program 2001). However, even after statin therapy asignificant number of patients still exhibit elevated levels of plasmatriglycerides and triglyceride-rich lipoproteins including very lowdensity lipoproteins (VLDL) and intermediate density lipoproteins (IDL)(Friday, Exp Biol Med (Maywood) 2003, 228(7):769-78; Quilliam et al., JManag Care Pharm 2004, 10(3):244-50). To treat this population ofpatients with concurrent high plasma triglyceride levels the ATPIII hasidentified lowering of triglyceride-rich cholesterol fractions(VLDL+IDL) as a secondary target of drug therapy (National CholesterolEducation Program 2001). Unfortunately treatment of such patients withfibrates, an approved class of triglyceride lowering drugs, haspotential adverse side effects, including the possibility of increasedLDL cholesterol as well as carrying the risk of fatal rhabdomyolysis, sothat combination therapy must proceed cautiously (National CholesterolEducation Program 2001). Similarly nicotinic acid, a second approvedtriglyceride lowering agent, is contraindicated in patients with insulinresistance and type II diabetes (Capuzzi et al., Curr Atheroscler Rep2000, 2(1):64-71). Taken together these observations highlight the needfor an effective therapeutic agent for the lowering of triglycerides andnon-HDL cholesterol in patients with cardiovascular disease, diabetes,and metabolic syndrome.

The maintenance of lipid homeostasis requires coordinate control ofcholesterol and triglyceride synthesis, transport, up-take, andexcretion. Interestingly, studies in human and in animal models haveuncovered a link between bile acids, the metabolic end-product ofcholesterol metabolism, and lipid homeostasis. Clinical studies in thelate 1970s exploring the effect of bile acids on cholesterol gallstonesdemonstrated that treatment with chenodeoxycholic acid (CDCA) reducesplasma triglyceride levels (Bateson et al., Br J Clin Pharmacol 1978,5(3):249-54; Iser and Sali, Drugs 1981, 21(2):90-119). In contrast,treatment with bile acid sequestrants, which deplete intestinal bileacids, increase triglycerides (Angelin et al., J Lipid Res 1978;19(8):1017-24). Importantly the bile acid-dependent decrease intriglycerides is mediated, at least in part, through a reduction in theproduction of VLDL (Hirokane et al., J Biol Chem 2004, 279(44):45685-92;Post et al., Arterioscler Thromb Vasc Biol 2004, 24(4):768-74; Sirventet al., FEBS Lett 2004, 566(1-3):173-7; Kang and Davis, Biochim BiophysActa 2000, 1529(1-3):223-30).

Atherosclerosis and its clinical consequences, including coronary heartdisease (CHD), stroke and peripheral vascular disease, represent a trulyenormous burden to the health care systems of the industrialized world.In the United States alone, approximately 13 million patients have beendiagnosed with CHD, and greater than one half million deaths areattributed to CHD each year. Further, this toll is expected to grow overthe next quarter century as an epidemic in obesity and diabetescontinues to grow.

It has long been recognized that in mammals, variations in circulatinglipoprotein profiles correlate with the risk of atherosclerosis and CHD.The clinical success of HMG-CoA reductase inhibitors, especially thestatins, in reducing coronary events is based on the reduction ofcirculating low density lipoprotein cholesterol (LDL-C), levels of whichcorrelate directly with an increased risk for atherosclerosis. Morerecently, epidemiologic studies have demonstrated an inverserelationship between high density lipoprotein cholesterol (HDL-C) levelsand atherosclerosis, leading to the conclusion that low serum HDL-Clevels are associated with an increased risk for CHD.

SUMMARY OF THE INVENTION

The present application relates to methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) at least one second agent thatis an CCR2/CCR5 antagonist, ASK1 inhibitor, DPP-IV inhibitor, caspaseprotease inhibitor, SGLT2 inhibitor, acetyl-CoA carboxylase (ACC)inhibitor, diacylglycerol acyltransferase-1 inhibitor, sodium-bile acidcotransporter-inhibitor, TLR-4 antagonist, PPAR alpha/delta agonist, orGLP-1 agonist, or a combination thereof.

The present application also relates to FXR modulators. Disclosed hereinare FXR modulatators, and pharmaceutical compositions that include suchFXR modulatators, for use in the treatment of diseases, disorders orconditions that would benefit from FXR modulation. In one aspect is theadministration of an FXR modulator described herein to a mammal in thetreatment of diseases, disorders or conditions that would benefit fromFXR modulation.

In an aspect of the invention are methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) a second agent that is a DPP-IVinhibitor. Disclosed herein, are methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) a second agent that is an SGLT2inhibitor. Disclosed herein, are methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) a second agent that is an ASK1inhibitor. Disclosed herein, are methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) a second agent that is a GLP-1agonist.

In some embodiments, the FXR modulator is a compound of Formula (I):

-   -   wherein:    -   R¹ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,        —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵,        —C(O)R¹⁴, —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹²,        —C(S)N(R¹¹)R¹², —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵,        —C(O)N(R¹³)N(R¹¹)R¹², —C(S)N(R¹³)N(R¹¹)R¹² and        —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;    -   R² is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

-   -   R⁹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R⁸ and        R⁹ together with the carbon atoms to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring or an        optionally substituted heteroaryl ring;    -   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹¹ and R¹² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or        optionally R¹¹ and R¹² together with the nitrogen atom to which        they are attached, form an optionally substituted        C₂-C₉heterocycloalkyl ring;    -   R¹⁵ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or        optionally R²¹ and R²² together with the nitrogen atom to which        they are attached, form an optionally substituted        C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or a pharmaceutically acceptable        salt, stereoisomer, or solvate thereof    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or    -   R²⁷ and R²⁸ together with the nitrogen atom to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring; or a pharmaceutically acceptable salt, stereoisomer, or        solvate thereof.

In some embodiments, the FXR modulator is a compound of Formula (II):

-   -   wherein:    -   R¹ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,        —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵,        —C(O)R¹⁴, —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹²,        —C(S)N(R¹¹)R¹², —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵,        —C(O)N(R¹³)N(R¹¹)R¹², —C(S)N(R¹³)N(R¹¹)R¹² and        —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;    -   R² is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶;

-   -   R⁹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R⁸ and        R⁹ together with the carbon atoms to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring or an        optionally substituted heteroaryl ring;    -   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹¹ and R¹² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or        optionally R¹¹ and R¹² together with the nitrogen atom to which        they are attached, form an optionally substituted        C₂-C₉heterocycloalkyl ring;    -   R¹⁵ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or        optionally R²¹ and R²² together with the nitrogen atom to which        they are attached, form an optionally substituted        C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or a pharmaceutically acceptable        salt, stereoisomer, or solvate thereof    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or    -   R²⁷ and R²⁸ together with the nitrogen atom to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring; or a pharmaceutically acceptable salt, stereoisomer, or        solvate thereof.

In some embodiments of a compound of Formula (I) or (II), R⁶ and R⁷ arehydrogen. In some embodiments of a compound of Formula (I) or (II), R⁴and R⁵ are each independently optionally substituted C₁-C₆alkyl. In someembodiments of a compound of Formula (I) or (II), R⁴ and R⁵ are methyl.In some embodiments of a compound of Formula (I) or (II), R³ is—C(O)R²⁰. In some embodiments of a compound of Formula (I) or (II), R³is —S(O)₂R²⁰. In some embodiments of a compound of Formula (I) or (II),R³ is —C(O)R²⁰ or —S(O)₂R²⁰; and R²⁰ is optionally substituted aryl. Insome embodiments of a compound of Formula (I) or (II), R³ is—C(O)N(R²¹)R²². In some embodiments of a compound of Formula (I) or(II), R³ is —C(O)N(R²¹)R²²; R²¹ is hydrogen and R²² is optionallysubstituted aryl. In some embodiments of a compound of Formula (I) or(II), R⁸ is —C(O)OR²⁵. In some embodiments of a compound of Formula (I)or (II), R⁸ is —C(O)OR²⁵ and R²⁵ is optionally substituted C₁-C₆alkyl.In some embodiments of a compound of Formula (I) or (II), R⁸ is—C(O)OR²⁵ and R²⁵ is methyl. In some embodiments of a compound ofFormula (I) or (II), R⁸ is —C(O)OR²⁵ and R²⁵ is ethyl. In someembodiments of a compound of Formula (I) or (II), R⁹ is hydrogen oroptionally substituted C₁-C₆alkyl. In some embodiments of a compound ofFormula (I) or (II), R⁹ is hydrogen. In some embodiments of a compoundof Formula (I) or (II), R⁹ is optionally substituted C₁-C₆alkyl. In someembodiments of a compound of Formula (I) or (II), R⁹ is C₁-C₆alkyl. Insome embodiments of a compound of Formula (I) or (II), R⁹ is methyl. Insome embodiments of a compound of Formula (I) or (II), R² is hydrogen.In some embodiments of a compound of Formula (I) or (II), R¹ ishydrogen. In some embodiments of a compound of Formula (I) or (II), R¹is C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, or optionallysubstituted C₂-C₆alkynyl.

In some embodiments, the FXR modulator is a compound of Formula (III):

-   -   wherein:    -   R¹ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,        —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵,        —C(O)R¹⁴, —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹²,        —C(S)N(R¹¹)R¹², —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵,        —C(O)N(R¹³)N(R¹¹)R¹², —C(S)N(R¹³)N(R¹¹)R¹² and        —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;    -   R⁴ and R⁵ are each independently optionally substituted        C₁-C₆alkyl;    -   R⁹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁵ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹¹ and R¹² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or        optionally R¹¹ and R¹² together with the nitrogen atom to which        they are attached, form an optionally substituted        C₂-C₉heterocycloalkyl ring;    -   R²⁵ is C₁-C₆alkyl;    -   R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring or an optionally        substituted heteroaryl ring;    -   n is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4;    -   t is 2, 3, or 4; or a pharmaceutically acceptable salt,        stereoisomer, or solvate thereof.

In some embodiments of a compound of Formula (III), R³⁰ is F. In someembodiments of a compound of Formula (III), R³⁰ is

In some embodiments of a compound of Formula (III), R³⁰ is

In some embodiments of a compound of Formula (III), t is 2; and each R³²and R³³ are hydrogen. In some embodiments of a compound of Formula(III), R³⁴ and R³⁵ together with the nitrogen atom to which they areattached form a C₂-C₉heterocycloalkyl ring. In some embodiments of acompound of Formula (III), R³⁴ and R³⁵ together with the nitrogen atomto which they are attached form a morpholinyl. In some embodiments of acompound of Formula (III), n is 1. In some embodiments of a compound ofFormula (III), R³¹ is halogen. In some embodiments of a compound ofFormula (III), R³¹ is F. In some embodiments of a compound of Formula(III), R⁴ and R⁵ are each methyl. In some embodiments of a compound ofFormula (III), R⁹ is hydrogen or optionally substituted C₁-C₆alkyl. Insome embodiments of a compound of Formula (III), R⁹ is hydrogen. In someembodiments of a compound of Formula (III), R⁹ is optionally substitutedC₁-C₆alkyl. In some embodiments of a compound of Formula (III), R⁹ isC₁-C₆alkyl. In some embodiments of a compound of Formula (III), R⁹ ismethyl.

In some embodiments of a compound of Formula (III), the FXR modulator isa compound of Formula (IIIa), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

In some embodiments of a compound of Formula (III), the FXR modulator isa compound of Formula (IIIb), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

In some embodiments, the FXR modulator is a compound of Formula (IV):

-   -   wherein:    -   R¹ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,        —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵,        —C(O)R¹⁴, —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹²,        —C(S)N(R¹¹)R¹², —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵,        —C(O)N(R¹³)N(R¹¹)R¹², —C(S)N(R¹³)N(R¹¹)R¹² and        —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;    -   R⁴ and R⁵ are each independently optionally substituted        C₁-C₆alkyl;    -   R⁹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁵ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹¹ and R¹² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or        optionally R¹¹ and R¹² together with the nitrogen atom to which        they are attached, form an optionally substituted        C₂-C₉heterocycloalkyl ring;    -   R²⁵ is C₁-C₆alkyl;    -   R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring or an optionally        substituted heteroaryl ring;    -   n is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4;    -   t is 2, 3, or 4; or a pharmaceutically acceptable salt,        stereoisomer, or solvate thereof.

In some embodiments of a compound of Formula (IV), R³⁰ is F. In someembodiments of a compound of Formula (IV), R³⁰ is

In some embodiments of a compound of Formula (IV), R³⁰ is

In some embodiments of a compound of Formula (IV), t is 2; and each R³²and R³³ are hydrogen. In some embodiments of a compound of Formula (IV),R³⁴ and R³⁵ together with the nitrogen atom to which they are attachedform a C₂-C₉heterocycloalkyl ring. In some embodiments of a compound ofFormula (IV), R³⁴ and R³⁵ together with the nitrogen atom to which theyare attached form a morpholinyl. In some embodiments of a compound ofFormula (IV), n is 1. In some embodiments of a compound of Formula (IV),R³¹ is halogen. In some embodiments of a compound of Formula (IV), R³¹is F. In some embodiments of a compound of Formula (IV), R⁴ and R⁵ areeach methyl. In some embodiments of a compound of Formula (IV), R⁹ ishydrogen or optionally substituted C₁-C₆alkyl. In some embodiments of acompound of Formula (IV), R⁹ is hydrogen. In some embodiments of acompound of Formula (IV), R⁹ is optionally substituted C₁-C₆alkyl. Insome embodiments of a compound of Formula (IV), R⁹ is C₁-C₆alkyl. Insome embodiments of a compound of Formula (IV), R⁹ is methyl.

In some embodiments of a compound of Formula (IV), the FXR modulator isa compound of Formula (IVa), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

In some embodiments of a compound of Formula (IV), the FXR modulator isa compound of Formula (IVb), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

In some embodiments of a compound of Formula (III) or (IV), R¹ ishydrogen. In some embodiments of a compound of Formula (III) or (IV), R¹is C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, or optionallysubstituted C₂-C₆alkynyl. In some embodiments of a compound of Formula(III) or (IV), R²⁵ is methyl. In some embodiments of a compound ofFormula (III) or (IV), R²⁵ is ethyl. In some embodiments of a compoundof Formula (III) or (IV), R²⁵ is isopropyl.

In some embodiments, the FXR modulator is a compound of Formula (V):

-   -   wherein:    -   R¹ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,        —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵,        —C(O)R¹⁴, —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹²,        —C(S)N(R¹¹)R¹², —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵,        —C(O)N(R¹³)N(R¹¹)R¹², —C(S)N(R¹³)N(R¹¹)R¹² and        —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;    -   R⁴ and R⁵ are each independently optionally substituted        C₁-C₆alkyl;    -   R⁹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁵ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹¹ and R¹² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or        optionally R¹¹ and R¹² together with the nitrogen atom to which        they are attached, form an optionally substituted        C₂-C₉heterocycloalkyl ring;    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, and optionally substituted C₁-C₆alkyl;    -   R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring or an optionally        substituted heteroaryl ring;    -   n is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4;    -   t is 2, 3, or 4; or a pharmaceutically acceptable salt,        stereoisomer, or solvate thereof.

In some embodiments of a compound of Formula (V), R³⁰ is F. In someembodiments of a compound of Formula (V), R³⁰ is

In some embodiments of a compound of Formula (V), R³⁰ is

In some embodiments of a compound of Formula (V), t is 2; and each R³²and R³³ are hydrogen. In some embodiments of a compound of Formula (V),R³⁴ and R³⁵ together with the nitrogen atom to which they are attachedform a C₂-C₉heterocycloalkyl ring. In some embodiments of a compound ofFormula (V), R³⁴ and R³⁵ together with the nitrogen atom to which theyare attached form a morpholinyl. In some embodiments of a compound ofFormula (V), n is 1. In some embodiments of a compound of Formula (V),R³¹ is halogen. In some embodiments of a compound of Formula (V), R³¹ isF. In some embodiments of a compound of Formula (V), R⁴ and R⁵ are eachmethyl. In some embodiments of a compound of Formula (V), R⁹ is hydrogenor optionally substituted C₁-C₆alkyl. In some embodiments of a compoundof Formula (V), R⁹ is hydrogen. In some embodiments of a compound ofFormula (V), R⁹ is optionally substituted C₁-C₆alkyl. In someembodiments of a compound of Formula (V), R⁹ is C₁-C₆alkyl. In someembodiments of a compound of Formula (V), R⁹ is methyl.

In some embodiments of a compound of Formula (V), the FXR modulator is acompound of Formula (Va), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

In some embodiments of a compound of Formula (V), the FXR modulator is acompound of Formula (Vb), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

In some embodiments, the FXR modulator is a compound of Formula (VI):

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally        substituted aryl, optionally substituted heteroaryl, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted        —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,        —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵,        —C(O)R¹⁴, —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹²,        —C(S)N(R¹¹)R¹², —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵,        —C(O)N(R¹³)N(R¹¹)R¹², —C(S)N(R¹³)N(R¹¹)R¹² and        —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;    -   R⁴ and R⁵ are each independently optionally substituted        C₁-C₆alkyl;    -   R⁹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹⁵ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R¹¹ and R¹² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or        optionally R¹¹ and R¹² together with the nitrogen atom to which        they are attached, form an optionally substituted        C₂-C₉heterocycloalkyl ring;    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, and optionally substituted C₁-C₆alkyl;

R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring or an optionally        substituted heteroaryl ring;    -   n is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4;    -   t is 2, 3, or 4; or a pharmaceutically acceptable salt,        stereoisomer, or solvate thereof.

In some embodiments of a compound of Formula (VI), R³⁰ is F. In someembodiments of a compound of Formula (VI), R³⁰ is

In some embodiments of a compound of Formula (VI), R³⁰ is

In some embodiments of a compound of Formula (VI), t is 2; and each R³²and R³³ are hydrogen. In some embodiments of a compound of Formula (VI),R³⁴ and R³⁵ together with the nitrogen atom to which they are attachedform a C₂-C₉heterocycloalkyl ring. In some embodiments of a compound ofFormula (VI), R³⁴ and R³⁵ together with the nitrogen atom to which theyare attached form a morpholinyl. In some embodiments of a compound ofFormula (VI), n is 1. In some embodiments of a compound of Formula (VI),R³¹ is halogen. In some embodiments of a compound of Formula (VI), R³¹is F. In some embodiments of a compound of Formula (VI), R⁴ and R⁵ areeach methyl. In some embodiments of a compound of Formula (VI), R⁹ ishydrogen or optionally substituted C₁-C₆alkyl. In some embodiments of acompound of Formula (VI), R⁹ is hydrogen. In some embodiments of acompound of Formula (VI), R⁹ is optionally substituted C₁-C₆alkyl. Insome embodiments of a compound of Formula (VI), R⁹ is C₁-C₆alkyl. Insome embodiments of a compound of Formula (VI), R⁹ is methyl.

In some embodiments of a compound of Formula (VI), the FXR modulator isa compound of Formula (VIa), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

In some embodiments of a compound of Formula (VI), the FXR modulator isa compound of Formula (VIb), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

In some embodiments of a compound of Formula (V) or (VI), R¹ ishydrogen. In some embodiments of a compound of Formula (V) or (VI), R¹is C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, or optionallysubstituted C₂-C₆alkynyl. In some embodiments of a compound of Formula(V) or (VI), R²⁵ and R²⁶ are independently hydrogen or C₁-C₆alkyl. Insome embodiments of a compound of Formula (V) or (VI), R²⁵ and R²⁶ arehydrogen. In some embodiments of a compound of Formula (V) or (VI), R²⁵and R²⁶ are independently C₁-C₆alkyl.

In some embodiments, the FXR modulator is a compound of Formula (VII):

-   -   wherein:    -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);

R² is selected from the group consisting of —CN, —C(O)OR²⁵,—C(O)N(R²⁵)R²⁶,

-   -    or R¹ and R² together with the carbon atoms to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring or an optionally substituted heteroaryl ring;    -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ together with the carbon atoms to which they are        attached, form an optionally substituted nitrogen containing        6-membered heteroaryl ring;    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R²¹ and        R²² together with the nitrogen atom to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring; or a pharmaceutically        acceptable salt, stereoisomer, or solvate thereof.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIIa), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIIb), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIIc), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIId), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIIe), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIIf), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIIg), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIIh), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIIi), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VII), the FXR modulator isa compound of Formula (VIIj), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹², and        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VIIa)-(VIIj), n is 0. Insome embodiments of a compound of Formula (VII) or (VIIa)-(VIIj), R⁶ andR⁷ are hydrogen. In some embodiments of a compound of Formula (VII) or(VIIa)-(VIIj), R³ is —C(O)N(R²¹)R²². In some embodiments of a compoundof Formula (VII) or (VIIa)-(VIIj), R³ is —C(O)N(R²¹)R²²; R²¹ is hydrogenand R²² is optionally substituted aryl. In some embodiments of acompound of Formula (VII) or (VIIa)-(VIIj), wherein R³ is —C(O)R²⁰. Insome embodiments of a compound of Formula (VII) or (VIIa)-(VIIj), R³ is—S(O)₂R²⁰. In some embodiments of a compound of Formula (VII) or(VIIa)-(VIIj), R³ is —C(O)R²⁰ or R³ is —S(O)₂R²⁰ and R²⁰ is optionallysubstituted aryl.

In some embodiments, the FXR modulator is a compound of Formula (VIII):

-   -   wherein:    -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

-   -    or R¹ and R² together with the carbon atoms to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring or an optionally substituted heteroaryl ring;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ together with the carbon atoms to which they are        attached, form an optionally substituted nitrogen containing        6-membered heteroaryl ring;    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring or an optionally        substituted heteroaryl ring;    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4; or a pharmaceutically acceptable salt,        stereoisomer, or solvate thereof.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIa), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIb), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIc), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIId), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIe), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIf), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIg), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIh), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIi), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIj), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

-   -   wherein:    -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments of a compound of Formula (VIIIa)-(VIIIj), n is 0. Insome embodiments of a compound of Formula (VIII) or (VIIIa)-(VIIIj), R³⁰is F. In some embodiments of a compound of Formula (VIII) or(VIIIa)-(VIIIj), R³⁰ is

In some embodiments of a compound of Formula (VIII) or (VIIIa)-(VIIIj),R³⁰ is

In some embodiments of a compound of Formula (VIII) or (VIIIa)-(VIIIj),t is 2; and each R³² and R³³ are hydrogen. In some embodiments of acompound of Formula (VIII) or (VIIIa)-(VIIIj), R³⁴ and R³⁵ together withthe nitrogen atom to which they are attached form aC₂-C₉heterocycloalkyl ring. In some embodiments of a compound of Formula(VIII) or (VIIIa)-(VIIIj), R³⁴ and R³⁵ together with the nitrogen atomto which they are attached form a morpholinyl. In some embodiments of acompound of Formula (VIII) or (VIIIa)-(VIIIj), p is 1. In someembodiments of a compound of Formula (VIII) or (VIIIa)-(VIIIj), R³¹ ishalogen. In some embodiments of a compound of Formula (VIII) or(VIIIa)-(VIIIj), R³¹ is F. In some embodiments of a compound of Formula(VIII) or (VIIIa)-(VIIIj), R⁶ and R⁷ are hydrogen. In some embodimentsof a compound of Formula (VIII) or (VIIIa)-(VIIIj), R⁴ and R⁵ are eachindependently optionally substituted C₁-C₆alkyl. In some embodiments ofa compound of Formula (VIII) or (VIIIa)-(VIIIj), R⁴ and R⁵ are methyl.In some embodiments of a compound of Formula (VIII) or (VIIIa)-(VIIIj),R² is —C(O)OR²⁵. In some embodiments of a compound of Formula (VIII) or(VIIIa)-(VIIIj), R² is —C(O)OR²⁵ and R²⁵ is optionally substitutedC₁-C₆alkyl. In some embodiments of a compound of Formula (VIII) or(VIIIa)-(VIIIj), R² is —C(O)OR²⁵ and R²⁵ is methyl. In some embodimentsof a compound of Formula (VIII) or (VIIIa)-(VIIIj), R² is —C(O)OR²⁵ andR²⁵ is ethyl. In some embodiments of a compound of Formula (VIII) or(VIIIa)-(VIIIj), R² is —C(O)OR²⁵ and R²⁵ is isopropyl. In someembodiments of a compound of Formula (VIII) or (VIIIa)-(VIIIj), R² is—C(O)N(R²⁵)R²⁶. In some embodiments of a compound of Formula (VIII) or(VIIIa)-(VIIIj), R¹ is hydrogen or optionally substituted C₁-C₆alkyl. Insome embodiments of a compound of Formula (VIII) or (VIIIa)-(VIIIj), R¹is hydrogen. In some embodiments of a compound of Formula (VIII) or(VIIIa)-(VIIIj), R¹ is optionally substituted C₁-C₆alkyl. In someembodiments of a compound of Formula (VIII) or (VIIIa)-(VIIIj), R¹ isC₁-C₆alkyl. In some embodiments of a compound of Formula (VIII) or(VIIIa)-(VIIIj), R¹ is methyl. In some embodiments of a compound ofFormula (VIII) or (VIIIa)-(VIIIj), R⁸ is hydrogen.

In some embodiments, the FXR modulator is a compound of Formula (XI) ora pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

-   -    or R¹ and R² together with the carbon atoms to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring or an optionally substituted heteroaryl ring;    -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ are each independently selected from the group        consisting of hydrogen, halogen, —CN, amino, alkylamino,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₃-C₈cycloalkyl, optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted aryl,        and optionally substituted heteroaryl;    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R²¹ and        R²² together with the nitrogen atom to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring.

In some embodiments, the FXR modulator is a compound of Formula (XII),or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

-   -    or R¹ and R² together with the carbon atoms to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring or an optionally substituted heteroaryl ring;    -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ are each independently selected from the group        consisting of hydrogen, halogen, —CN, amino, alkylamino,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₃-C₈cycloalkyl, optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted aryl,        and optionally substituted heteroaryl;    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R²¹ and        R²² together with the nitrogen atom to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring.

In some embodiments of a compound of Formula (XI) or (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R⁴and R⁵ are hydrogen. In some embodiments of a compound of Formula (XI)or (XII), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof, R⁴ and R⁵ are C₁-C₆alkyl. In some embodiments of acompound of Formula (XI) or (XII), or a pharmaceutically acceptablesalt, stereoisomer, or solvate thereof, R⁴ and R⁵ are methyl. In someembodiments of a compound of Formula (XI) or (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R⁶and R⁷ are hydrogen. In some embodiments of a compound of Formula (XI)or (XII) R⁶ is —C(O)N(R²⁷)R²⁸ and R⁷ are hydrogen. In some embodimentsof a compound of Formula (XI) or (XII), or a pharmaceutically acceptablesalt, stereoisomer, or solvate thereof, R² is —C(O)OR²⁵. In someembodiments of a compound of Formula (XI) or (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R²is —C(O)OR²⁵ and R²⁵ is optionally substituted C₁-C₆alkyl. In someembodiments of a compound of Formula (XI) or (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R²is —C(O)OR²⁵ and R²⁵ is methyl. In some embodiments of a compound ofFormula (XI) or (XII), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof, R² is —C(O)OR²⁵ and R²⁵ is ethyl. Insome embodiments of a compound of Formula (XI) or (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R²is —C(O)OR²⁵ and R²⁵ is isopropyl. In some embodiments of a compound ofFormula (XI) or (XII), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof, R² is —C(O)N(R²⁵)R²⁶. In someembodiments of a compound of Formula (XI) or (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R¹is hydrogen. In some embodiments of a compound of Formula (XI) or (XII),or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof,R¹ is optionally substituted C₁-C₆alkyl. In some embodiments of acompound of Formula (XI) or (XII), or a pharmaceutically acceptablesalt, stereoisomer, or solvate thereof, R¹ is —CH₃. In some embodimentsof a compound of Formula (XI) or (XII), or a pharmaceutically acceptablesalt, stereoisomer, or solvate thereof, R³ is —C(O)N(R²¹)R²². In someembodiments of a compound of Formula (XI) or (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen, and R²² is optionally substitutedaryl. In some embodiments of a compound of Formula (XI) or (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R³is —C(O)R²⁰. In some embodiments of a compound of Formula (XI) or (XII),or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof,R³ is —C(O)R²⁰ and R²⁰ is optionally substituted aryl. In someembodiments of a compound of Formula (XI) or (XII), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R³is —S(O)₂R²⁰. In some embodiments of a compound of Formula (XI) or(XII), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof, R³ is —S(O)₂R²⁰ and R²⁰ is optionally substituted aryl.

In some embodiments of a compound of Formula (VIII), the FXR modulatoris a compound of Formula (VIIIa), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof, or a compound of Formula (XII), theFXR modulator is a compound of Formula (XIIa), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:

wherein:

-   -   R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In some embodiments of a compound of Formula (XIa) or (XIIa), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R³⁰is halogen. In some embodiments of a compound of Formula (XIa) or(XIIa), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof, R³⁰ is F. In some some embodiments of a compound of Formula(XIa) or (XIIa), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof, R³⁰ is

In some embodiments of a compound of Formula (XIa) or (XIIa), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, R³⁰is

In some embodiments of a compound of Formula (XIa) or (XIIa), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, t is2. In some embodiments of a compound of Formula (XIa) or (XIIa), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, p is0. In some embodiments of a compound of Formula (XIa) or (XIIa), or apharmaceutically acceptable salt, stereoisomer, or solvate thereof, pis 1. In some embodiments of a compound of some embodiments of acompound of Formula (XIa) or (XIIa), or a pharmaceutically acceptablesalt, stereoisomer, or solvate thereof, R³¹ is F.

In an aspect of the invention, are FXR modulatators, and pharmaceuticalcompositions that include such FXR modulatators, for use in thetreatment of diseases, disorders or conditions that would benefit fromFXR modulation. In one aspect is the administration of an FXR modulatordescribed herein to a mammal in the treatment of diseases, disorders orconditions that would benefit from FXR modulation. In some embodimentsis the administration of an FXR modulator described herein to a mammalin the treatment of diseases, disorders or conditions that would benefitfrom FXR modulation, wherein the FXR modulator is(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof.

In an aspect of the invention, are methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) a second agent that is a DPP-IVinhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, and omarigliptin.

In an aspect of the invention, are methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) a second agent that is an SGLT2inhibitor selected from canagliflozin, empagliflozin, dapagliflozin,ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozinetabonate, and ertugliflozin.

In an aspect of the invention, is a method of treating a metabolicdisorder in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof.

In an aspect of the invention, are methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) a second agent that is an ASK1inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride).

In an aspect of the invention, are methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) a second agent that is a GLP-1agonist selected from exenatide, liraglutide, lixisenatide, albiglutide,dulaglutide, taspoglutide, and semaglutide.

In an aspect of the invention, are methods of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator; and (b) at least one second agent thatis a DPP-IV inhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1agonist, or a combination thereof; wherein the metabolic disorder isnonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis, obesity, diabetic nephropathy or nephrotic syndrome. Insome embodiments, the metabolic disorder is nonalcoholic steatohepatitis(NASH).

In some embodiments is a method of treating a metabolic disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is nonalcoholic steatohepatitis (NASH),hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease,atherosclerotic disease events, atherosclerotic cardiovascular disease,Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity,hyperglycemia, cholestasis, or obesity.

CROSS-REFERENCE TO RELATED APPLICATIONS

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

The present application relates to FXR modulatators, and pharmaceuticalcompositions that include such FXR modulatators, for use in thetreatment of diseases, disorders or conditions that would benefit fromFXR modulation. In one aspect is the administration of an FXR modulatordescribed herein to a mammal in the treatment of diseases, disorders orconditions that would benefit from FXR modulation. In some embodimentsis the administration of an FXR modulator described herein to a mammalin the treatment of diseases, disorders or conditions that would benefitfrom FXR modulation, wherein the FXR modulator is(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof.

Disclosed herein, are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof.

FXR Biology

The Farnesoid X receptor (FXR; also referred to as NR1H4; nuclearreceptor nomenclature committee 1999) is a member of the steroid andthyroid hormone nuclear receptor superfamily of ligand regulatedtranscription factors. FXR is highly expressed in the liver, kidney,intestines and the adrenals and at lower levels in the vasculature(Forman et al., Cell 1995, 81(5):687-93). Bile acids, the end-productsof cholesterol catabolism, bind directly to the ligand binding pocket ofFXR and act as agonists to increase the receptor's ability to activatetranscription (Makishima et al., Science 1999, 284(5418):1362-5 1999; Miet al., Mol Cell 2003, 11(4):1093-100; Parks et al., Science 1999,284(5418):1365-8; Wang et al., Mol Cell 1999, 3(5):543-53). In responseto bile acid binding FXR regulates a network of genes that control thesynthesis, transport, and catabolism of bile acids, but alsotriglycerides and cholesterol (Chawla et al., Cell 2000, 103(1):1-4;Repa and Mangelsdorf, Annu Rev Cell Dev Biol 2000, 16:459-81). Thus FXRfunctions as a regulator of lipid metabolism by modifying geneexpression in response to quantitative changes in the metabolism andbreakdown of cholesterol. In support of this conclusion, studies inhumans and in animals have demonstrated that modifying bile acid levelscan have profound effects on plasma triglyceride and cholesterol levels(Angelin et al., J Lipid Res 1978, 19(8):1017-24; Bateson et al., Br JClin Pharmacol 1978, 5(3):249-54; Iser and Sali, Drugs 1981,21(2):90-119; Kuroki et al., Lipids 1999, 34(8):817-23).

FXR was originally cloned and classified as an orphan member of thenuclear hormone receptor superfamily based upon DNA sequence homology.Initial studies identified farnesol as a ligand for FXR (Forman et al.,Cell 1995, 81(5):687-93), however, subsequent analysis demonstrated thatbile acids bind directly to the ligand binding domain of FXR andfunction as activators of the receptor's transcriptional activity. Thebinding affinities of bile acids for FXR is near the concentration thatthese compounds reach in animals (μM) lending support to the idea thatbile acids function as endogenous ligands in vivo (Makishima et al.,Science 1999, 284(5418):1362-5 1999; Mi et al., Mol Cell 2003,11(4):1093-100; Parks et al., Science 1999, 284(5418):1365-8; Wang etal., Mol Cell 1999, 3(5):543-53). Activation of FXR upon bile acidbinding leads to transcriptional down-regulation of cholesterol7α-hydroxylase (CYP7A1), the rate limiting enzyme in the conversion ofcholesterol to bile acids. Inhibition of CYP7A1 by bile acids occurs viaFXR-dependent induction of the small heterodimeric partner (SHP; alsoreferred to as NR0B2, Nuclear Receptor Nomenclature Committee 1999), atranscriptional repressor. Binding sites for FXR have been identified inthe SHP promoter indicating that this gene is a direct target of FXR (Luet al., Mol Cell 2000, 6(3):507-15; Goodwin et al., Mol Cell 2000,6(3):517-26). Thus bile acid-dependent repression of CYP7A1 is indirectand results from a transcriptional cascade initiated by FXR. A similarSHP-dependent mechanism has been described for the bile acid repressionof another gene involved in bile acid synthesis, CYP8B1 (sterol 12ahydroxylase; Yang et al., Biochim Biophys Acta 2002, 1583(1):63-73), andfor the sodium/taurocholate cotransporter peptide (NTCP) which is one oftwo major transporters responsible for bile acid up-take by the liver(Denson et al., Gastroenterology 2001; 121(1):140-7). In contrast thegenes encoding the bile salt export pump (BSEP) and the multidrugresistance protein 2 (MDR2) are directly induced by FXR, once again viabinding sites in their respective promoter regions (Ananthanarayanan etal., J Biol Chem 2001, 276(31):28857-65; Huang et al., J Biol Chem 2003,278(51):51085-90; Liu et al., J Clin Invest 2003, 112(11):1678-87).These two transporters are required for the transfer of bile acids(BSEP) and phospholipids (MDR2) out of the hepatocytes into the biliarysystem. This pattern of FXR-dependent gene expression defines a classicfeedback loop where high levels of bile acids inhibit new bile acidsynthesis and bile acid uptake while simultaneously promoting their ownclearance.

The regulation of bile acid synthesis and transport by FXR has importantimplications for cholesterol metabolism. Repression of CYP7A1 and CYP8B1impacts the bile acid synthetic pathway at two important points. First,inhibition of CYP7A1, the rate limiting enzyme, can decrease synthesisand reduce the size of the bile acid pool. Second, inhibition of CYP8B1alters bile acid composition by favoring the production of morehydrophilic bile acids such as CDCA (muricholic acid/MCA in mice)(Russell, Annu Rev Biochem 2003, 72:137-74). Importantly, studies inmice have demonstrated that the more hydrophilic bile acids are lessefficient at promoting intestinal cholesterol absorption (Wang et al.,Am J Physiol Gastrointest Liver Physiol 2003, 285(3):G494-502).

Although regulating bile acid synthesis may contribute to theFXR-dependent effects on lipid metabolism, gene expression analysisindicates that FXR also directly influences triglyceride synthesis andVLDL production. FXR agonists induce the genes encoding fibroblastgrowth factor 19 (Holt et al., Genes Dev 2003, 17(13):1581-91),acylation stimulating protein (a proteolytic product of complement C3;Li et al., J Biol Chem 2005, 280(9):7427-34), apolipoprotein CII (Kastet al., Mol Endocrinol 2001, 15(10):1720-8), and apolipoprotein AV(Prieur et al., J Biol Chem 2003, 278(28):25468-80) all of which areknown to promote the clearance and oxidation of fat carried bytriglyceride rich lipoproteins. Additionally FXR inhibits expression ofthe genes encoding apolipoprotein CIII (Claudel et al., Gastroenterology2003, 125(2):544-55), an inhibitor of lipoprotein lipase, and the sterolresponse element binding protein 1c (SREBP1c; Watanabe et al., J ClinInvest 2004, 113(10):1408-18). SREBP1c, a member of basichelix-loop-helix family of transcription factors, functions as a mastertranscriptional regulator of the enzymes required for fatty acidsynthesis (Osborne, J Biol Chem 2000, 275(42):32379-82). Taken togetherthe genetic network controlled by FXR defines a signal transductionsystem poised to respond to changes in fat and carbohydrate dietaryintake-driven lipid homeostasis. High levels of cholesterol in the liverwill lead to increased production of bile acids and subsequentactivation of FXR. In response to this activating signal FXR decreasesthe absorption of cholesterol in the intestine, favoring excretion,increases the clearance and oxidation of triglycerides and decreases thesynthesis of fatty acids leading to a reduction in VLDL production.

The ability of FXR to regulate bile-acid synthesis, clearance andhomeostasis as supported by the ability of FXR ligands to promote thetransport of bile acid and phospholipids out of the liver suggests autility for such compounds in diseases of disturbed bile acid andcholesterol flow such as Primary Biliary cirrhosis and NASH. In thisregard FXR agonists have been shown to be effective in animal models ofcholestasis, gallstones, and liver fibrosis (Liu et al., J Clin Invest2003, 112(11):1678-87; Fiorocci et al., Gastroenterology 2004,127(5):1497-512; Fiorocci et al., J Pharmacol Exp Ther 2005,313(2):604-12; Fiorocci et al., J Pharmacol Exp Ther 2005,314(2):584-95).

DPP-IV Biology

Dipeptidyl peptidase-IV (DPP-IV) is a serine protease, which selectivelycleaves the N-terminal dipeptide from the penultimate position ofGlucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-LikePeptide (GLP-1) thus making them inactive (Diabetes Obes Metab., 10,376-387, 2008; Diabetes Care, 30, 1979-1987, 2007). GLP-1 is an incretinhormone secreted by intestinal L-Cells in response to food intake. Theactive GLP-1 stimulates insulin secretion, inhibits glucagon release andslows gastric emptying, which together contributes for effective glucosehomeostasis in patients with type 2 diabetes. Inhibition of DPP-IVactivity extends the duration of action of endogenous GLP-1, therebyexhibiting all the favorable attributes of GLP-1 (Lancet, 368,1696-1705, 2006; Horm Metab Res., 36 (11-12), 867-76, 2004). DPP-IVinhibitors offer a number of potential advantages over existing diabetestherapies, including a lowered risk of hypoglycemia, weight gain and thepotential for regeneration and differentiation of pancreatic beta-cells(Handbook Exp Pharmacol., 203, 53-74, 2011; Curr Med Res Opin., 23(4),919-31, 2007). Because of these multiple benefits of GLP-1 mediatedglucose homeostasis, orally bioavailable DPP-IV inhibitors has beendeveloped as promising therapeutic agents for the treatment of type 2diabetes (Am. J. Ther., 15(5), 484-91, 2008). The therapeutic potentialof DPP-IV inhibitors for the treatment of type 2 diabetes have beendiscussed and reviewed extensively (Exp. Opin. Invest. Drugs, 12,87-100, 2003; Exp. Opin. Ther. Patents, 13, 499-510, 2003; Exp. Opin.Investig. Drugs, 13, 1091-1102, 2004; Curr. Opin. Drug DiscoveryDevelopment, 11, 512-532, 2008 and Trends in Molecular Medicine, 14,161-168, 2008).

SGLT2 Biology

Sodium-dependent glucose cotransporters (SGLTs) couple the transport ofglucose against a concentration gradient with the simultaneous transportof Na+ down a concentration gradient. Two important SGLT isoforms havebeen cloned and identified as SGLT1 and SGLT2. SGLT1 is located in thegut, kidney, and heart where its expression regulates cardiac glucosetransport. SGLT1 is a high-affinity, low-capacity transporter andtherefore accounts for only a small fraction of renal glucosereabsorption. In contrast, SGLT2 is a low-affinity, high-capacitytransporter located exclusively at the apical domain of the epithelialcells in the early proximal convoluted tubule. In healthy individuals,greater than 99% of the plasma glucose that filtered in the kidneyglomerulus is reabsorbed, resulting in less than 1% of the totalfiltered glucose being excreted in urine. It is estimated that 90% ofrenal glucose reabsorption is facilitated by SGLT2; the remaining 10% islikely mediated by SGLT1 in the late proximal straight tubule. Geneticmutations in SGLT2 lead to increased renal glucose excretion of as muchas 140 g/day depending on the mutation with no apparent adverse effectson carbohydrate metabolism. Since SGLT2 appears to be responsible forthe majority of renal glucose reabsorption based on human mutationstudies, it has become a target of therapeutic interest (Lee, J. et al.Bioorg. Med. Chem. 2010, 18, 2178-2194; Van den Heuvel, L. P. et al.Hum. Genet. 2020, 111, 544-547).

ASK1 Biology

Mitogen-activated protein kinase (MAPK) signaling cascades couplediverse extracellular and intracellular queues to appropriate cellularstress responses, including cell growth, differentiation, inflammation,and apoptosis (Kumar, S., et al. (2003) Nat. Rev. Drug Dis. 2:717-726;Pimienta, G., et al. (2007) Cell Cycle, 6: 2826-2632). MAPKs exist inthree groups, MAP3Ks, MAP2Ks, and MAPKs, which are sequentiallyactivated. MAPK3s directly respond to environmental signals andphosphorylate MAP2Ks, which in turn phosphorylate specific MAPKs. MAPKsthen mediated the appropriate cellular response by phosphorylatingcellular substrates, including transcription factors that regulate geneexpression. Apoptosis signal-regulating kinase 1 (ASK1) is a member ofthe mitogen-activated protein kinase kinase kinase (“MAP3K”) family thatactivates the c-Jun N-terminal protein kinase (“JNK”) and p38 MAP kinase(Ichijo, H., et al. (1997) Science, 275, 90-94). ASK1 is activated by avariety of stimuli including oxidative stress, reactive oxygen species(ROS), LPS, TNF-alpha, FasL, ER stress, and increased intracellularcalcium concentrations (Hattori, K., et al. (2009) Cell Comm. Signal.7:1-10; Takeda, K., et al. (2007) Annu. Rev. Pharmacol. Toxicol. 48:1-8.27; Nagai, H., et al. (2007) J. Biochem. Mol. Biol. 40:1-6). ASK1undergoes activation via autophosphorylation at Thr838 in response tothese signals and in turn phosphorylates MAP2Ks, such as MKK3/6 andMKK4/7, which then phosphorylate and activate p38 and JNK MAPKs,respectively. ASK2 is a related MAP3K that shares 45% sequence homologywith ASK1 (Wang, X. S., et al. (1998) Biochem. Biophys. Res. Commun.253, 33-37. Although ASK2 tissue distribution is restricted, in somecell types ASK1 and ASK2 have been reported to interact and functiontogether in a protein complex (Takeda, K., et al. (2007) J. Biol. Chem.282: 7522-7531; Iriyama, T., et al. (2009) Embo J. 28: 843-853) In nonstressed conditions, ASK1 is kept in an inactive state through bindingto its repressor Thioredoxin (Trx) (Saitoh, M., et al. (1998) Embo J.17:2596-2606), and through association with AKT (Zhang, L., et al.(1999) Proc. Natl. Acad. Sci. U.S.A 96:8511-8515). Phosphorylation ofASK1 protein can lead to apoptosis or other cellular responses dependingon the cell type. ASK1 activation and signaling have been reported toplay an important role in a broad range of diseases includingneurodegenerative, cardiovascular, inflammatory, autoimmunity, andmetabolic disorders. In addition, ASK1 has been implicated in mediatingorgan damage following ischemia and reperfusion of the heart, brain, andkidney (Watanabe et al. (2005) BBRC 333, 562-567; Zhang et al., (2003)Life Sci 74-37-43; Terada et al. (2007) BBRC 364: 1043-49). Emergingevidence suggests that ASK2, either alone or in a complex with ASK1, mayplay important roles in human diseases as well. Therefore, therapeuticagents that function as inhibitors of ASK1 and ASK2 signaling complexeshave the potential to remedy or improve the lives of patients sufferingfrom such conditions.

GLP-1 Biology

Glucagon and GLP-1 are members of structurally related peptide hormonefamily (secretin family). Glucagon and GLP-1 constitute a highlyhomologous set of peptides because these two hormones originate from acommon precursor, preproglucagon, which upon tissue-specific processingleads to production of GLP-1 predominantly in the intestine and glucagonin the pancreas (Jiang, G., et al., Am. J. Physiol. Endocrinol. Metab.,2003, 284, E671-678). The receptors for these two peptides arehomologous (58% identity) and belong to the class B family of G-proteincoupled receptors (GPCRs). Class-B GPCRS is also called as the secretinreceptor family, which consist of 15 peptide-binding receptors inhumans. GPCR receptors comprise an extracellular N-terminal domain of100-160 residues, connected to a juxtamembrane domain (J-domain) ofseven membrane-spanning co-helices with intervening loops and aC-terminal tail (Brubaker, P. L., et al., Receptors Channels, 2002, 8,179). Class B GPCRs are activated by endogenous peptide ligands ofintermediate size, typically 30-40 amino acids (Hoare, S. R. J., DrugDiscovery Today, 2005, 10, 423; Gether, U., Endocrine Reviews, 2000, 21,90).

Glucagon is a 29-amino acid peptide hormone processed from proglucagonin pancreatic alpha-cells by PC2. Glucagon acts via a seventransmembrane GPCRs, consisting of 485 amino acids. Glucagon is releasedinto the bloodstream when circulating glucose is low. The mainphysiological role of glucagon is to stimulate hepatic glucose output,thereby leading to increase in glycemia (Tan, K., et al., Diabetologia,1985, 28, 435). Glucagon provides the major counter regulatory mechanismfor insulin in maintaining glucose homeostasis in vivo. Glucagon and itsreceptor represent potential targets for the treatment of diabetes.Antagonising glucagon action by blocking the action of the secretedglucagon at glucagon receptor (glucagon antagonist) or by inhibiting(suppressing) the glucagon production itself represents a new avenue forintervention of diabetes and metabolic disorders (Unson, C. G., et al.,Peptides, 1989, 10, 1171; Parker, J. C., Diabetes, 2000, 49, 2079;Johnson, D. G., Science, 1982, 215, 1115).

The GLP-1 (7-36) amide is a product of the preproglucagon gene, which issecreted from intestinal L-cells, in response to the ingestion of food.The physiological action of GLP-1 has gained considerable interest.GLP-1 exerts multiple actions by stimulating insulin secretion frompancreatic beta-cells, in a glucose dependent manner (insulinotropicaction). GLP-1 lowers circulating plasma glucagon concentration, byinhibiting its secretion (production) from alpha-cells (Drucker D. J.,Endocrinology, 2001, 142, 521-527). GLP-1 also exhibits properties likestimulation of beta-cell growth, appetite suppression, delayed gastricemptying and stimulation of insulin sensitivity (Nauck, M. A., Horm.Metab. Res., 2004, 36, 852).

CCR2/CCR5 Antagonist Biology

The chemokine system comprises more than 20 different chemokinereceptors, which belong to the class A or rhodopsin-like family of Gprotein-coupled receptors (GPCRs). Almost 50 chemokine ligands play acritical role in the immune system, mediating the migration anddifferentiation of immune cells during homeostasis and inflammation.Dysregulation of this system can lead to a variety of differentpathologies, including inflammatory and autoimmune diseases. (Bot et al.Scientific Reports 7, Article number: 52 (2017)doi:10.10381/s41598-017-00104-4

Fibrosis results from a sustained inflammatory response to chronic organinjury and is characterized by the deposition of extracellular matrixproteins, including collagen types 1 and 3. Hepatic fibrosis isassociated with chronic liver disease, a significant global burden thatcontributes to cirrhosis and hepatocellular carcinoma. Likewise, renalfibrosis is a common manifestation of chronic kidney disease. Theinflammatory response to hepatocyte injury plays a key role in hepaticfibrogenesis and involves recruitment of bone marrow-derived monocytesand macrophages to the site of injury, which is triggered by theactivation of resident macrophages. In turn, infiltratingmonocytes/macrophages amplify this immune response by producinginflammatory cytokines and chemokines, which further promote recruitmentof inflammatory cells and upregulate the activation of hepatic stellate:cells (HSCs). Fibrogenic cytokines (e.g. transforming growth factor-beta[TGF-beta]), produced by activated macrophages, promotetransdifferentiation of HSCs into myofibroblasts, which are the primarysource of scar-forming matrix proteins, including fibrillar), collagentypes I and 3, and the contractile protein alpha-smooth muscle actin(alpha-SMA). (Lefebvre F, Moyle O, Reshef R, Richman L P, Thompson M,Hong F, et al. (2016) Antifibrotic Effects of the Dual CCR2/CCR5Antagonist Cenicriviroc in Animal Models of Liver and Kidney Fibrosis.PLoS ONE 11(6): e0158156. https://doi.org/10.1371/journal.pone.0158156)

Recruitment of extra-hepatic inflammatory cells to the site of hepaticinjury is largely mediated by interactions between chemokines and theirreceptors. Monocytes, KCs and HSCs can express C—C chemokine receptortypes 2 (CCR2) and 5 (CCR5) on their surface. (Lefebvre et al. 2016https://doi.org/10.1371/journal.pone.0158156). Examples of drugs whichare considered CCR2/CCR5 antagonist therapeutics include, but are notlimited to, cenicriviroc (CVC), aplaviroc, vicriviroc (e.g.,5-({4-[(3S)-4-{2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine),maraviroc (e.g., 4,4′-difluorocyclohexylamide) and cochilioquinone A.

Caspase Protease Inhibitor Biology

Caspases are the key effector molecules of the physiological deathprocess known as apoptosis, although some are involved in activation ofcytokines, rather than cell death. They are one of approximately 20families of cysteine proteases. Caspases exist in most mammalian cellsas inactive precursors (zymogens) that kill the cell once activated andcan be controlled in two ways. The processing and activation of acaspase can be regulated by molecules such as FADD, APAF-1, Bcl-2 familymembers, FLIP and IAPs. Active caspases can be controlled by a varietyof inhibitors that directly interact with the protease. (Ekert, P. G.;Silke, J.; Vaux, D. L. Cell Death Differ. 1999; 6(11):1081-6). Examplesof drugs considered to be caspase protease inhibitors include, but arenot limited to, emricasan, Q-VD-Oph, DEVD-CHO, zVAD-FMK, Pralnacasan(Vertex), and M867 (Merck).

Acetyl-CoA Carboxylase (ACC) Inhibitor Biology

Acetyl-CoA carboxylase is a biotin-dependent enzyme that catalyzes theirreversible carboxylation of acetyl-CoA to produce malonyl-CoA throughits two catalytic activities, biotin carboxylase (BC) andcarboxyltransferase (CT). ACC is a large, multi-domain enzyme in theendoplasmic reticulum of most eukaryotes. The most important function ofACC is to provide the malonyl-CoA substrate for the biosynthesis offatty acids. The human genome contains the genes for two different ACCs:ACACA and ACACB. (Widmer, J. Biochem J. 1996, 15: 316—Part 3, 915-922.)Examples of drugs include, but are not limited to,(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-2-methylpropanoicacid(“NDI-010976” or “GS-0976”) (Gilead), 5-(tetradecyloxy)-2-furoic acid(“TOFA”), Medica 16, and(3R)-1′-(9-anthracenylcarbonyl)[1,4′-bipiperidin]-3-yl]-4-morpholinyl-methanone(“CP-640186”) (Cayman Chemical).

Diacylglycerol Acyltransferase-1 Inhibitor Biology

Diacylglycerol acyltransferase-1 is an enzyme involved in the formationof triyglcerides and is highly expressed in human fat metabolism sitessuch as intesting, liver, and adipose. Dietary triglycerides cannot beabsorbed directly in the gastrointestinal tract and are broken down intofree fatty acids and monglycerol in the intestine by pancreatic lipase.Inhibition of diacylglycerol acyltransferase-1 has shown to reduce fatstorage in mammals leading to reduction of body weight. Examples ofdrugs include, but are not limited to, pradigastat (“LCQ908”), VK5211, A922500, amidepsine A, and amidepisne D.

Apical Sodium-Bile Acid Cotransporter-Inhibitor (ASBT) Biology

Apical sodium-dependent bile acid transporter (ASBT or ABAT, SLC10A2) isthe second member of the SLC10A family of solute carrier proteins andhas important physiological functions as a bile acid transporter fromthe lumen of the gastrointestinal tract to the liver via the portalvein. Classes of therapeutics include dihydropyridine calcium channelblockers, and HMG-CoA reductase inhibitors (statins). Examples of drugsinclude, but are not limited to, volixibat (“LUM-002/SHP626”), LJN 452(Novartis), GSK2330672 (GSK), AZD-7806, S-8921, AK-105, BARI-1741,SC-435 or SC-635.

TLR-4 Antagonist Biology

TLR-4 is a protein that in humans is encoded by the TLR4 gene. TLR4 is atransmembrane protein, member of the toll-like receptor family, whichbelongs to the pattern recognition receptor (PRR) family. Its activationleads to an intracellular signaling pathway NF-κB and inflammatorycytokine production which is responsible for activating the innateimmune system. It is most well known for recognizing lipopolysaccharide(LYS), a component present in many Gram-negative bacteria (e.g.Neisseria spp.) and select Gram-positive bacteria. Its ligands alsoinclude several viral proteins, polysaccharide, and a variety ofendogenous proteins such as low-density lipoprotein, beta-defensins, andheat shock protein. Examples of drugs which are considered TLR-4antagonists include, but are not limited to, JKB-121, amitriptyline,imipramine, naloxone, LPS-RS, cyclbenzprine, mianserin, naltrexone,propentofylline, ketotitfen, ibudilast, (+)-naltrexone, tapentradol, anderitoran.

PPAR Alpha/Delta Agonist Biology

Examples of drugs which are considered PPAR alpha/delta agonistsinclude, but are not limited to, GFT505, amphipathic carboxylic acids(e.g., clofibrate, gemfibrozil, ciprofibrate, bezafibrate, andfenofibrate), GW501516, aleglitzar, muraglitazar, tesaglitazar, andsaroglitazar.

Statins

Statins, also known as HMG-CoA reductase inhibitors, are a class oflipid-lowering medications. Statins have been found to reducecardiovascular disease (CVD) and mortality in those who are at highrisk. Statins are effective for treating CVD in the early stages of adisease (secondary prevention) and in those at elevated risk but withoutCVD (primary prevention). Examples of drugs include, but are not limitedto, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin,rosuvastatin, and simvastatin.

FXR Agonists and Nonalcoholic Fatty Liver Disease (NAFLD) andNonalcoholic Staetohepatitis (NASH)

NAFLD is a well-recognized component of the metabolic syndrome,characterized by increased serum levels of lipids and glucose, increasedincidence of type II diabetes, atherosclerosis, hypertension, and breastand colon cancer. Although many NAFLD cases have benign prognosis, somedevelop NASH, liver fibrosis, cirrhosis, and tumor. The disruption ofthe Nr1h4 gene in mice showed that FXR deficiency results in fatty liverformation following feeding with a high-cholesterol diet (Sinal C J etal. Cell. 2000; 102:731-744). In addition, FXR deficiency renders themice more susceptible to NASH formation in a diet-induced obese mousemodel (Kong B et al. J Pharmacol Exp Ther. 2009; 328:116-122). The exactmechanism by which FXR deficiency enhances NAFLD to NASH transition isnot clear, but likely involves a FXR-dependent disruption of lipid andbile acid homeostasis, which leads to lipid accumulation and bileacid-induced chronic injury in the liver. FXR deficiency also results inincreased collagen expression, and increased collagen expression is anearly event in liver fibrosis development. In agreement, activation ofFXR has been shown to suppress liver fibrosis development. Advancedliver fibrosis leads to cirrhosis, portal hypertension and liverfailure. The treatment of choice is liver transplantation because noeffective pharmaceutical agents are available to halt or reverse liverfibrosis.

The effect of FXR activation on the development and protection againstNASH has been investigated in animal models. Feeding mice a methionineand choline-deficient (MCD) diet is a well-established nutritional modelof NASH resulting in serum elevation of alanine aminotransferase (ALT)and aspartate aminotransferase (AST), and liver histologicalabnormalities similar to human NASH, including hepatic steatosis,lobular inflammation, and pericellular fibrosis. C57BL/6 mice were fedan MCD diet and treated with or without WAY-362450 (a synthetic FXRagonist) for 4 weeks. The elevations of serum ALT and AST induced by theMCD diet were markedly reduced with WAY-362450 treatment. Moreover, thehepatoprotective effects of WAY-362450 were abolished in FXR^(−/−) micefed an MCD diet. These results indicate that FXR agonists may be usefulfor the treatment NASH (Zhang S et al. J. Hepatol 2009; 51:380-8).

In a rabbit model of the metabolic syndrome, a high-fat diet resulted inan increase in visceral fat, fasting glycemia and glucose intolerance.Treatment with OCA (INT-747, an FXR agonist) along with the high-fatdiet normalized visceral fat fasting glucose levels, and improvedglucose tolerance. The effect of OCA on insulin resistance anddevelopment of hepatic steatosis has been studied in Zucker fa/fa obeserats (Cipriani S, Mencarelli A, Palladino G, et al. J Lipid Res 2010;51:771-84), a model for NAFLD with a loss-of-function mutation of theleptin receptor. These rats exhibit hyperphagia and hyperleptinemia anddevelop obesity, insulin resistance, diabetes, and hepatic steatosis. Inthis study, in comparison to lean rats, fa/fa rats on a normal dietdeveloped insulin resistance and hepatic steatosis. Administration ofOCA reversed insulin resistance and hepatic steatosis and protectedagainst body weight gain and liver and muscle fat deposition. Moreover,FXR activation resulted in a reduction of liver expression of genesinvolved in fatty acid synthesis, lipogenesis and gluconeogenesis. Inmuscle, FXR activation reduced free fatty acid synthesis.

Recently, the results of the Farnesoid X nuclear receptor ligand OCA inNASH treatment (the FLINT) trial were reported (Neuschwander-Tetri B Aet al. Farnesoid X nuclear receptor ligand obeticholic acid fornon-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre,randomised, placebo-controlled trial. Lancet 2014). In this multicenter,double-blinded, placebo controlled clinical trial, a total of 283patients with biopsy-proven NASH were randomized to receive either OCA25 mg orally daily or placebo for 72 weeks. The primary outcome measurewas improvement in NAFLD activity score by at least two points withoutworsening of fibrosis from baseline to the end of treatment. At the timeof analysis of the primary outcome, 110 patients in the OCA arm and 109patients in the placebo arm were included in the analysis. At 72 weeksof treatment, the percentage of patients who demonstrated histologicalimprovement in the OCA and placebo arm was 45% and 21%, respectively. Adecrease in the high-density lipoprotein (HDL) and an increase in thetotal cholesterol and low-density lipoprotein (LDL) was observed inpatients in the OCA arm compared to placebo. These results suggest thatOCA might be beneficial in preventing progression of NASH.

FXR and Inflammatory Bowel Disease (IBD)

IBD, which primarily includes ulcerative colitis (UC) and Crohn'sdisease (CD), represents a group of chronic disorders characterized bygastrointestinal tract inflammation. Although many details of IBD havebeen explored, the exact pathogenetic mechanisms of IBD have not beenfully elucidated. At present, IBD is generally believed to result fromimbalance of gut microbiota, epithelial dysfunction, and aberrantmucosal immune response.

Recently, FXR has been implicated to participate in immune modulationand barrier function in the intestine. FXR alleviates inflammation andpreserves the integrity of the intestinal epithelial barrier in manyways by regulating the extent of the inflammatory response, maintainingthe integrity and function of the intestinal barrier, and preventingbacterial translocation in the intestinal tract.

First, FXR plays an important role in the mucosal immune response,thereby exerting strong influence on immunoregulation. Vavassori et al.(J Immunol. 2009; 183:6251-6261) noticed that Fxr^(−/−) mice displayedsignificantly elevated pro-inflammatory cytokine mRNA expression in thecolon. In two complementary murine models (intra-rectal administrationof trinitrobenzensulfonic acid (TNBS) and oral administration ofdextrane sodium sulfate (DSS)), concurrent administration of the potentsynthetic FXR ligand 6-ECDCA repressed the expression of variousproinflammatory cytokines, chemokines and their receptors in wild type,but not Fxr^(−/−) mice. In addition, Raybould et al. (J Physiol. 2012;590:441-446) showed that FXR activation by INT-747 prevented DSS- andTNBS-induced intestinal inflammation, with improvement of colitissymptoms, inhibition of epithelial permeability, and reduced goblet cellloss. Furthermore, FXR activation inhibited proinflammatory cytokineproduction in vivo in the mouse colonic mucosa, and ex vivo in differentimmune cell populations. These results provide strong support for theinvolvement of FXR in IBD due to counter-regulatory effects on cells ofinnate immunity. FXR ligands exert anti-inflammatory activities byantagonizing other signaling pathways, in part through the interactionwith other transcription factors, including activator protein-1 (AP-1),and signal transducers and activators of transcription 3 (STAT3).

Second, FXR has been implicated in barrier function by regulatingintestinal antibacterial growth. Gut microbiota play important roles inpathogen defense, immunity, and nutrient harvest. Recent evidencesuggests that there is a regulatory relationship between the developmentof IBD and altered gut microbiota. It has been demonstrated that BAs andgut microbiota are closely related to each other. Gut microbiota areinvolved in the biotransformation of BAs through deconjugation,dehydroxylation, and reconjugation of BAs. BAs have antimicrobialactivities by damaging the bacterial cell membrane, thus inhibitingbacterial outgrowth.

The administration of bile or conjugated BAs to ascitic cirrhotic ratsor obstructive jaundice rats eliminates intestinal bacterial overgrowth,and decreases bacterial translocation and endotoxemia. Inagaki et al.(Proc Natl Acad Sci USA. 2006; 103:3920-3925) provides an explanationfor this protective effect of BAs by demonstrating that intestinal FXRhas a crucial role in limiting bacterial overgrowth and thus protectingthe intestine from bacterial-induced damage. They show that mice lackingFXR experience bacterial overgrowth, increase intestinal permeabilityand contain large amounts of bacteria in mesenteric lymph nodes, as wellas inflammation of the intestinal walls. However, activation ofintestinal FXR by GW4064 leads to the identification of several novelintestinal FXR target genes, including those encoding angiogenin,carbonic anhydrase 12 and inducible nitric oxide synthase, which havebeen reported to have antibacterial properties. The cytokine IL-18 isalso induced by FXR stimulation. IL-18 stimulates resistance to an arrayof pathogens, including intracellular and extracellular bacteria andmycobacteria, and appears to have a protective role during the early,acute phase of mucosal immune response. These results are consistentwith the idea that FXR is critical for controlling intestinal bacterialgrowth, which has significant implications for maintaining a competentbarrier, thereby contributing to the prevention of intestinalinflammation.

FXR and Bile Acid Diarrhea (BAD) and Irritable Bowel Syndrome (IBS)

Bile acids are increasingly implicated in the pathogenesis of functionalGI disorders. New mechanisms have recently been described in theirritable bowel syndrome, chronic diarrhea and chronic idiopathicconstipation. Identification of bile acid signaling through farnesoid Xreceptor (FXR) has led to the development of new, directly actingtherapeutic agents. Despite these advances primary bile acid diarrhea(BAD) remains under-recognized partly because of the lack of a widelyavailable diagnostic test. Functional gastrointestinal disorders (FGID)are common and constitute a significant proportion of consultations inboth primary and secondary care. The most prevalent FGIDs are theirritable bowel syndrome (IBS) and functional dyspepsia, with aprevalence of around 20% each, regardless of the nationality of thepopulation. A recent study using Rome III criteria found that 42% ofattendees in the gastroenterology outpatient clinic met the criteria fora functional lower GI diagnosis. Of these patients, 24.5% met thecriteria for IBS-diarrhea (IBS-D), 6.1% functional diarrhea (FD), 22.1%IBS-constipation, and 22.1% chronic idiopathic constipation. Over thelast decade, understanding of the pathogenesis of these conditions hasadvanced and a clear relationship between bile acids (BAs) and theseFGIDs have become apparent.

FGF-19 stimulation by obeticholic acid (Zhang J H et al. Am. J. Physiol.2013; 304:G940-G948) provides an opportunity to reverse the deficiencywhich is considered one of the factors leading to excessive hepatocyteBA synthesis. This treatment was associated with improved stoolfrequency and consistency in a preliminary study of patients with BAD(Johnston I M et al. Gastroenterology. 2013; 144(Suppl. 144):S60). Giventhe observation that BAs chronically downregulate colonic secretoryfunction in colonic epithelial cells, an effect that may serve tofacilitate normal colonic absorptive function, it is intriguing to notethat an FXR agonist, GW4064, induced nuclear translocation of thereceptor in T84 cells, attenuated Cl⁻ secretory responses to both Ca²⁺and cAMP-dependent agonists, and reduced ovalbumin-induced diarrhea andcholera toxin-induced intestinal fluid accumulation secretion in mice invivo. These observations suggest that FXR agonists may be efficacious inthe treatment of BAD through restoration of FGF-19 production andexertion of antisecretory actions on the colonic epithelium (Mroz M S etal. Gut. 2014 May; 63(5):808-17).

FXR Agonists and Cholestatic Liver Diseases (Primary Biliary Cirrhosis(PBC), Primary Sclerosing Cholangitis (PSC) and Biliary Atresia)

PBC is a chronic, progressive, cholestatic liver disease characterizedhistologically by destruction of intrahepatic bile ducts andserologically by the presence of the antimitochondrial antibodies(AMAs). AMA is a highly disease-specific autoantibody, rarely found inindividuals without PBC. Epidemiological studies have reported aprevalence of PBC ranging from 19 to 365 cases per million, and anincidence of 4 to 58 cases per million persons-years. PBC may lead tohepatic fibrosis, cirrhosis, and eventually liver failure. PBC is animportant indication for liver transplantation in the United States andEurope. Currently, the only therapy approved by the United States Foodand Drug Administration (US FDA) is ursodeoxycholic acid (UDCA). Severalrandomized controlled clinical trials have shown that long-termadministration of UDCA in PBC patients delays histological progressionto cirrhosis and prolongs survival without liver transplantation.However, up to 40% of PBC patients have incomplete response to UDCA(158). Therefore, there is a critical need for other effective therapiesfor PBC patients who are at high risk for progressive disease.

PSC is a progressive disease of the liver characterized by cholestasisand ongoing destruction of intra- and extra-hepatic bile ducts, leadingultimately to fibrosis, cirrhosis, and liver failure. The diagnosis ofPSC is made in the setting of cholestasis and cholangiographic evidenceof intra- and/or extra-hepatic biliary ductal structuring. Small-ductPSC is a variant of PSC which is characterized by cholestatic andhistological evidence of PSC but normal cholangiography. PSC canprogress to liver fibrosis, cirrhosis, and ultimately liver failure. PSCis an important risk factor for cholangiocarcinoma (CCA), which is themost common primary biliary malignancy, and the second most commonprimary liver cancer after HCC. CCA is a very aggressive disease, oftendiagnosed in late stages. The percentage of CCA patients who survive 5years after diagnosis is only 10%.

Biliary atresia is a progressive obliterative cholangiopathy thatpresents in infancy with jaundice due to biliary obstruction. Despitethe use of surgical hepatic portoenterostomy (HPE) to reestablish bileflow, biliary atresia progresses to end-stage liver disease in 80% ofpatients over a variable length of time. Approximately one-half ofaffected infants will require liver transplantation in the first twoyears of life due to complications of cirrhosis and cholestasis,including severe malnutrition, ascites, portal hypertension andcoagulopathy. The remainder of children with biliary atresia may livemany years with their native livers, despite the chronic, progressivecirrhosis that develops.

In a Wistar rat model of cholestasis, OCA promoted bile flow andprotected the hepatocytes against acute necrosis caused byadministration of LCA (Pellicciari R et al. J Med Chem 2002;45:3569-72). In another rodent model of bile duct ligated (BDL) rats,the administration of OCA reduced liver fibrosis and α-collagen 1,transforming growth factor-β1 (TGF-β1), and tissue metalloproteinaseinhibitor-1 (Fiorucci S et al. Gastroenterology 2004; 127:1497-512).Collectively, these results indicate that FXR activation could bebeneficial in patients with cholestatic liver diseases.

Initial results from a 1-year phase III clinical trial of OCA in PBCpatients were reported in the International Liver Congress in April2014. A total of 217 patients with PBC whom previously had an inadequateresponse to UDCA were randomly assigned to receive placebo, OCA 10 mgdaily, or OCA 5 mg daily titrated to 10 mg daily. The primary endpointwas a composite endpoint of achieving a serum ALP activity of less than1.67 times the upper limit of normal, a total bilirubin within normallimits, and at least a 15% decrease in serum ALP. The proportion ofpatients meeting the primary endpoint was: 47% in the 10 mg OCA groupand 46% in the 5-10 mg OCA group vs. only 10% in the placebo group. Inaddition, both OCA dose groups met secondary endpoints of improvementsin other liver function parameters, GG, ALT and total bilirubin.Together, these results indicate that OCA could be an effective therapyfor patients with PBC. Currently, a phase II clinical trial of OCA inPSC is ongoing.

FXR and Atherosclerosis

FXR regulates lipid homeostasis and deficiency of FXR in mice increasessystemic and liver lipid levels. However, FXR deficiency has been shownto increase atherosclerotic plaque formation in male ApoE knockout micebut protect female ApoE mice from atherosclerotic plaque formation (GuoG L et al. Biochim Biophys Acta. 2006; 1761:1401-1409; Zhang Y et al.Arterioscler Thromb Vasc Biol. 2006; 26:2316-2321; and Hanniman E A etal. J Lipid Res. 2005; 46:2595-2604). The reduction of atheroscleroticplaque in the aorta area of female mice may be due to a decreased CD36expression and foam cell formation. CD36 is a long-chain fatty acidtransporter and is mainly responsible for taking up oxidized LDL intomacrophages. Lipid-laden macrophages become foam cells, the hall markfor atherosclerosis plaque development. This gender difference in therole of FXR in atherosclerosis development indicates again that FXR mayinteract with estrogen-related pathway(s) to modulate biologicalresponses.

FXR and Hypertriglyceridemia

The relationship between BAs (bile acids) and TG (triglyceride)metabolism was identified in the 1970s. The first evidence came from theobservation that the administration of BAs, such as CDCA for thetreatment of gallstones, resulted in decreased circulating TG levels;conversely, patients treated with BA-sequestering resins were found tohave increased serum TG and VLDL levels. Moreover, patients withmonogenic familial hypertriglyceridemia displayed a defect in ileal BAabsorption, whereas individuals with decreased BA synthesis due to aCYP7A1 deficiency exhibited elevated serum TG concentrations. Theseclinical observations suggest a direct relationship between BAs and TGmetabolism. The importance of FXR in TG metabolism was further confirmedin FXR-deficient mice, which exhibited marked hepatosteatosis andhypertriglyceridemia. In addition, FXR heterozygous mice demonstratedhepatosteatosis and hyperlipidemia following short-time high-fat diet(HFD) feeding. The TG lowering effects of endogenous and synthetic FXRagonists have been evaluated in other rodent models as well. Forinstance, CA prevented hepatic TG accumulation and VLDL secretion inKK-A(y) mice, a mouse model of hypertriglyceridemia (Watanabe M et al. JClin Invest 2004; 113: 1408-18). Moreover, the synthetic FXR agonistGW4064 was able to prevent liver steatosis in obese mice, such as theob/ob and db/db models (Zhang Y et al. Proc Natl Acad Sci USA 2006; 103:1006-11).

FXR and Diabetes, Diabetic Nephropathy and Glomerulosclerosis

Diabetes is the leading cause of end-stage renal disease in developedcountries. In spite of excellent glucose and blood pressure control,including administration of angiotensin converting enzyme inhibitorsand/or angiotensin II receptor blockers, diabetic nephropathy stilldevelops and progresses. Diabetic nephropathy is the most common renalcomplication of diabetes and the leading cause of end-stage renaldisease. The pathogenesis of diabetic nephropathy is complex andinvolves activation of multiple pathways leading to kidney damage,including the polyol pathway, advanced glycation end products, oxidativestress, proinflammatory cytokines, and profibrotic growth factors. Inaddition, an important role for altered lipid metabolism has beenrecently recognized in diabetic kidney disease. In this condition, thereis increased renal expression of sterol regulatory element bindingproteins 1 and 2 (SREBP-1 and SREBP-2), transcription factors thatmediate increased fatty acid and cholesterol synthesis, resulting intriglyceride and cholesterol accumulation in the kidney and areassociated with inflammation, oxidative stress, fibrosis, andproteinuria. A critical role for SREBP-1 was established by determiningthat SREBP-1 transgenic mice develop glomerulosclerosis and proteinuriain the absence of alterations in serum glucose or lipids, and thatSREBP-1c knockout mice are protected from the renal effects of ahigh-fat diet (Sun L et al. J Biol Chem 2002; 277:18919-18927 and JiangT et al. J Biol Chem 2005; 280:32317-32325). Modulation of SREBPs maytherefore represent a rational approach to prevent diabetic renalcomplications. Previous studies have shown that FXR agonists decreaseSREBP-1c expression in the kidney (Jiang T et al. Diabetes 2007;56:2485-2493 and Wang X X et al. Am J Physiol Renal Physiol 2009;297:F1587-F1596).

Treatment of db/db mice with type 2 diabetes (Jiang T et al. Diabetes.2007; 56:2485-2493), DBA/2J mice with diet-induced obesity and insulinresistance (Wang X X et al. Am J Physiol Renal Physiol. 2009;297:F1587-1596), and DBA/2J mice with streptozotocin-induced type 1diabetes (Wang X X, et al. Diabetes 2010; 59:2916-2927) with FXRagonists have shown renal protective effects. These experimental modelsof diabetic nephropathy showed improvements in proteinuria,glomerulosclerosis, tubulointerstitial fibrosis, and macrophageinfiltration following treatment with FXR activating agonists. Theserenal protective effects are mediated by effects on lipid metabolism,oxidative stress, and on the production of proinflammatory cytokines andprofibrotic growth factors. FXR agonists inhibit expression of SREBP-1and carbohydrate response element binding protein (ChREBP) in the kidneyresulting in decreased fatty acid synthesis and triglycerideaccumulation. FXR agonists also inhibit SREBP-2 resulting in decreasedcholesterol synthesis and accumulation in the kidney. These studiessuggest that FXR agonists can prevent the progression of kidney diseasein mouse models of type 1 diabetes mellitus, diet induced obesity andinsulin resistance, and type 2 diabetes mellitus.

FXR and Cholesterol Gallstone Disease (CGD)

Gallstone disease is one of the most frequent and costly digestivediseases in western countries, as its prevalence in adults ranges from10% to 15%. About 75% of the gallstones in the United States andwesternized countries, including Italy are cholesterol gallstones.Cholesterol gallstones are associated with well-known risk factors, suchas obesity, type 2 diabetes, dyslipidaemia, and hyperinsulinaemia, whichare often components of the metabolic syndrome epidemic, whichprevalence is greater than 35% in the adult pupulation and continues torise in westernized countries. A complex genetic basis plays a key rolein determining individual predisposition to develop cholesterolgallstones in response to environmental factors. Some “gallstone genes”might also play a potential role, including some genes governing thenuclear bile acid receptors such as farnesoid X receptor (FXR).

Moschetta et al. (Nat Med 2004; 10:1352-1358) hypothesized that FXR mayplay a critical role in the prevention of CGD by helping to maintain theproper solubilization of cholesterol in bile. To this end, stimulationof FXR using synthetic ligands could be useful in the prevention andtreatment of CGD. In the first part of the study, Moschetta et al.demonstrates the role of FXR in the development of CGD. Age-matchedwild-type and FXR^(−/−) mice were fed a lithogenic diet for 1 week,after which the gallbladder bile and expression of known FXR and LXRtarget genes were analyzed. Inspection of the gallbladder and bileshowed increases in inflammation, bile salt hydrophobicity, bileturbidity, and presence of cholesterol monohydrate crystals in the FXRnull mice, all phenotypical of CGD. Furthermore, bile salt andphospholipid levels were found to be significantly lower in the FXR nullmice due to a lack of FXR-mediated expression of Abcb11 and Abcb4.Conversely, cholesterol levels were not significantly altered, becauseregulation of the cholesterol transporters Abcg5 and Abcg8 through LXRoccurred independently of FXR. Consequently, the cholesterol saturationindex was increased in the FXR null mice, driving the early developmentof cholesterol monohydrate crystals. In the second part of the study,Moschetta et al. expanded their findings by demonstrating thatstimulation of FXR with a synthetic agonist can prevent the onset ofCGD. Here, CGD-susceptible C57L and FXR^(−/−) mice were fed a lithogenicdiet supplemented with the synthetic FXR ligand GW4064 or vehiclecontrol for 1 week. As expected, examination of the gallbladder and bileindicated onset of CGD in the vehicle-treated C57L and FXR null mice aswell as the GW4064-treated FXR null mice. Interestingly, two of the fivevehicle-treated C57L mice evidenced more advanced disease sequelaecompared with the FXR null mice, suggesting that mechanisms in additionto those mediated by FXR may contribute to the increased susceptibilityof these mice to CGD. However, GW4064 treatment prevented CGD onset inthe C57L mice through FXR-mediated upregulation of Abcb11 and Abcb4,increasing transport of bile salts and phospholipids to the bile,reducing of the cholesterol saturation index, and providing protectionfrom cholesterol monohydrate crystal formation.

However, maintenance of cholesterol and bile acid homeostasis in mice issomewhat different from that of humans. The bile acid pool of mice ismore hydrophilic than that of man and thus is less effective inactivating FXR. Control of CYP7A1-mediated bile acid synthesis fromcholesterol in mice is dominated by feed-forward activation through LXR,whereas in humans LXR is not functional in this capacity. Instead,control of bile acid synthesis in humans is dominated by feedbackrepression of CYP7A1 through FXR and other means. Thus in humans bileacid synthesis from cholesterol is primarily a means to maintain bileacid homeostasis, whereas in the mouse it is a means for removal ofcholesterol.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

“Amino” refers to the —NH₂ radical.

“Cyano” or “nitrile” refers to the —CN radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Oxime” refers to the ═N—OH substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a linear or branched hydrocarbon chain radical, whichis fully saturated, has from one to thirty carbon atoms, and is attachedto the rest of the molecule by a single bond. Alkyls are linear orbranched. Alkyls comprising any number of carbon atoms from 1 to 30 areincluded. An alkyl comprising up to 30 carbon atoms is referred to as aC₁-C₃₀ alkyl, likewise, for example, an alkyl comprising up to 12 carbonatoms is a C₁-C₁₂ alkyl. An alkyl comprising up to 6 carbons is a C₁-C₆alkyl. Alkyls (and other moieties defined herein) comprising othernumbers of carbon atoms are represented similarly. Alkyl groups include,but are not limited to, C₁-C₃₀ alkyl, C₁-C₂₀ alkyl, C₁-C₁₅ alkyl, C₁-C₁₀alkyl, C₁-C₈ alkyl, C₁-C₆ alkyl, C₁-C₄alkyl, C₁-C₃ alkyl, C₁-C₂ alkyl,C₂-C₈ alkyl, C₃-C₈ alkyl, C₄-C₈ alkyl, and C₅-C₁₂ alkyl. Representativealkyl groups include, but are not limited to, methyl, ethyl, n-propyl,1-methylethyl (isopropyl), n-butyl, i-butyl, s-butyl, n-pentyl,1,1-dimethylethyl (t-butyl), 2-ethylpropyl, and the like. Representativelinear alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, n-butyl, n-pentyl and the like. Unless stated otherwisespecifically in the specification, an alkyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each R^(f) is independently alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl or heteroarylalkyl.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In certain embodiments, an alkenyl comprises two to sixcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, trimethylsilanyl, —OR^(a),—SR^(a), —OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), oximo,—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f),—N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2)and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, and each R^(f) is independently alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In certain embodiments, an alkynyl comprises two to six carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a), —N(R^(a))₂,—C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f),—OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where tis 1 or 2), —S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where tis 1 or 2) and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2) where each R^(a)is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl or heteroarylalkyl, and each R^(f) is independently alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group arethrough one carbon in the alkylene chain or through any two carbonswithin the chain. In certain embodiments, an alkylene comprises one toeight carbon atoms (e.g., C₁-C₈ alkylene). In other embodiments, analkylene comprises one to five carbon atoms (e.g., C₁-C₅ alkylene). Inother embodiments, an alkylene comprises one to four carbon atoms (e.g.,C₁-C₄ alkylene). In other embodiments, an alkylene comprises one tothree carbon atoms (e.g., C₁-C₃ alkylene). In other embodiments, analkylene comprises one to two carbon atoms (e.g., C₁-C₂ alkylene). Inother embodiments, an alkylene comprises one carbon atom (e.g., C₁alkylene). In other embodiments, an alkylene comprises five to eightcarbon atoms (e.g., C₅-C₈ alkylene). In other embodiments, an alkylenecomprises two to five carbon atoms (e.g., C₂-C₅ alkylene). In otherembodiments, an alkylene comprises three to five carbon atoms (e.g.,C₃-C₅ alkylene). Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted by one ormore of the following substituents: halo, cyano, nitro, oxo, thioxo,imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)—R^(a),—N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each R^(f) is independently alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl or heteroarylalkyl.

“Aminoalkyl” refers to a radical of the formula —R^(c)—N(R^(a))₂ or—R^(c)—N(R^(a))—R^(c), where each R^(c) is independently an alkylenechain as defined above, for example, methylene, ethylene, and the like;and each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

“Alkoxy” refers to a radical of the formula —OR^(a) where R^(a) is analkyl radical as defined. Unless stated otherwise specifically in thespecification, an alkoxy group may be optionally substituted asdescribed above for alkyl.

“Aryl” refers to a radical derived from a hydrocarbon ring systemcomprising hydrogen, 6 to 30 carbon atoms and at least one aromaticring. The aryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused (when fused with acycloalkyl or heterocycloalkyl ring, the aryl is bonded through anaromatic ring atom) or bridged ring systems. Aryl radicals include, butare not limited to, aryl radicals derived from the hydrocarbon ringsystems of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene,azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene,s-indacene, indane, indene, naphthalene, phenalene, phenanthrene,pleiadene, pyrene, and triphenylene. Unless stated otherwisespecifically in the specification, an aryl group is optionallysubstituted by one or more of the following substituents: alkyl,alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl,aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), heteroaryl, —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocycloalkyl (optionally substituted with one or more alkyl groups),heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, or two R^(a)attached to the same nitrogen atom are combined to form aheterocycloalkyl, each R^(b) is independently a direct bond or astraight or branched alkylene or alkenylene chain, and R^(c) is astraight or branched alkylene or alkenylene chain, and where each of theabove substituents is unsubstituted unless otherwise indicated.

“Aryloxy” refers to a radical bonded through an oxygen atom of theformula —O-aryl, where aryl is as defined above.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, methylene, ethylene,and the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —Re-aryl, where Re is analkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Cycloalkyl” or “carbocycle” refers to a stable, non-aromatic,monocyclic or polycyclic carbocyclic ring, which may include fused (whenfused with an aryl or a heteroaryl ring, the cycloalkyl is bondedthrough a non-aromatic ring atom) or bridged ring systems, which issaturated or unsaturated. Representative cycloalkyls include, but arenot limited to, cycloalkyls having from three to fifteen carbon atoms(C₃-C₁₅ cycloalkyl), from three to ten carbon atoms (C₃-C₁₀ cycloalkyl),from three to eight carbon atoms (C₃-C₈ cycloalkyl), from three to sixcarbon atoms (C₃-C₆ cycloalkyl), from three to five carbon atoms (C₃-C₅cycloalkyl), or three to four carbon atoms (C₃-C₄ cycloalkyl).Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycycliccycloalkyls include, for example, adamantyl, norbornyl, decalinyl,bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin,bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and7,7-dimethyl-bicyclo[2.2.1]heptanyl. Unless otherwise statedspecifically in the specification, the cycloalkyl is optionallysubstituted by one or more substituents independently selected fromalkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro,optionally substituted aryl, optionally substituted aralkyl, optionallysubstituted aralkenyl, optionally substituted aralkynyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Cycloalkylalkyl” refers to a radical of the formula —R^(c)-cycloalkylwhere R^(c) is an alkylene chain as defined above. The alkylene chainand the cycloalkyl radical are optionally substituted as defined above.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure. When the fused ring is a heretocycloalkylring or a heteroaryl ring, any carbon atom on the existing ringstructure which becomes part of the fused heretocycloalkyl ring or thefused heteroaryl ring may be replaced with a nitrogen atom.

“Heteroalkyl” refers to a straight or branched hydrocarbon chain alkylradical containing no unsaturation, having from one to fifteen carbonatoms (e.g., C₁-C₁₅ alkyl) consisting of carbon and hydrogen atoms andone or two heteroatoms selected from O, N, and S, wherein the nitrogenor sulfur atoms may be optionally oxidized and the nitrogen atom may bequaternized. The heteroatom(s) may be placed at any position of theheteroalkyl group including between the rest of the heteroalkyl groupand the fragment to which it is attached. The heteroalkyl is attached tothe rest of the molecule by a single bond. Unless stated otherwisespecifically in the specification, a heteroalkyl group is optionallysubstituted by one or more of the following substituents: halo, cyano,nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, —OR^(a), —SR^(a),—OC(O)—R^(a), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a), —C(O)N(R^(a))₂,—N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f),—N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a) (where t is1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2) and —S(O)_(t)N(R^(a))₂(where t is 1 or 2) where each R^(a) is independently hydrogen, alkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl,and each R^(f) is independently alkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl,heteroaryl or heteroarylalkyl.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In someembodiments, halogen refers to chloro or fluoro.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like. Unless stated otherwise specifically inthe specification, a haloalkyl group may be optionally substituted.

“Haloalkoxy” similarly refers to a radical of the formula —OR^(a) whereR^(a) is a haloalkyl radical as defined. Unless stated otherwisespecifically in the specification, a haloalkoxy group may be optionallysubstituted as described below.

“Heterocycloalkyl” or “heterocycle” refers to a stable 3- to 24-memberednon-aromatic ring radical comprising 2 to 23 carbon atoms and from oneto 8 heteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur. Unless stated otherwise specifically in thespecification, the heterocycloalkyl radical may be a monocyclic,bicyclic, tricyclic or tetracyclic ring system, which may include fused(when fused with an aryl or a heteroaryl ring, the heterocycloalkyl isbonded through a non-aromatic ring atom) or bridged ring systems; andthe nitrogen, carbon or sulfur atoms in the heterocycloalkyl radical maybe optionally oxidized; the nitrogen atom may be optionally quaternized;and the heterocycloalkyl radical may be partially or fully saturated.Representative heterocycloalkyls include, but are not limited to,heterocycloalkyls having from two to fifteen carbon atoms (C₂-C₁₅heterocycloalkyl), from two to ten carbon atoms (C₂-C₁₀heterocycloalkyl), from two to eight carbon atoms (C₂-C₈heterocycloalkyl), from two to six carbon atoms (C₂-C₆heterocycloalkyl), from two to five carbon atoms (C₂-C₅heterocycloalkyl), or two to four carbon atoms (C₂-C₄ heterocycloalkyl).Examples of such heterocycloalkyl radicals include, but are not limitedto, aziridinyl, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl,methyl-2-oxo-1,3-dioxol-4-yl, 2-oxo-1,3-dioxol-4-yl,1,1-dioxidotetrahydro-2H-thiopyranyl, tetrahydro-2H-thiopyranyl, andtetrahydro-2H-pyranyl. The term heterocycloalkyl also includes all ringforms of the carbohydrates, including but not limited to themonosaccharides, the disaccharides and the oligosaccharides. Unlessotherwise noted, heterocycloalkyls have from 2 to 8 carbons in the ring.It is understood that when referring to the number of carbon atoms in aheterocycloalkyl, the number of carbon atoms in the heterocycloalkyl isnot the same as the total number of atoms (including the heteroatoms)that make up the heterocycloalkyl (i.e. skeletal atoms of theheterocycloalkyl ring). Unless stated otherwise specifically in thespecification, a heterocycloalkyl group is optionally substituted by oneor more of the following substituents selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionallysubstituted aryl, optionally substituted aralkyl, optionally substitutedaralkenyl, optionally substituted aralkynyl, optionally substitutedcycloalkyl, optionally substituted cycloalkylalkyl, optionallysubstituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain, and where each of the above substituents isunsubstituted unless otherwise indicated.

“Heterocycloalkyllalkyl” refers to a radical of the formula—R^(c)-heterocycloalkyl where R^(c) is an alkylene chain as definedabove. If the heterocycloalkyl is a nitrogen-containingheterocycloalkyl, the heterocycloalkyl is optionally attached to thealkyl radical at the nitrogen atom. The alkylene chain of theheterocycloalkylslkyl radical is optionally substituted as defined abovefor an alkylene chain. The heterocycloalkyl part of theheterocycloalkylalkyl radical is optionally substituted as defined abovefor a heterocycloalkyl group.

“Heterocycloalkylalkoxy” refers to a radical bonded through an oxygenatom of the formula —O—R^(c)-heterocycloalkyl where R^(c) is an alkylenechain as defined above. If the heterocycloalkyl is a nitrogen-containingheterocycloalkyl, the heterocycloalkyl is optionally attached to thealkyl radical at the nitrogen atom. The alkylene chain of theheterocycloalkylalkoxy radical is optionally substituted as definedabove for an alkylene chain. The heterocycloalkyl part of theheterocycloalkylalkoxy radical is optionally substituted as definedabove for a heterocycloalkyl group.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen,phosphorous and sulfur, and at least one aromatic ring. In someembodiments, the heteroaryl is a 5-membered heteroaryl. In someembodiments, the heteroaryl is a 6-membered heteroaryl. For purposes ofthis invention, the heteroaryl radical may be a monocyclic, bicyclic,tricyclic or tetracyclic ring system, which may include fused (whenfused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl isbonded through an aromatic ring atom) or bridged ring systems; and thenitrogen, carbon or sulfur atoms in the heteroaryl radical may beoptionally oxidized; the nitrogen atom may be optionally quaternized.Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwisespecifically in the specification, a heteroaryl group is optionallysubstituted by one or more of the following substituents selected fromalkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl,oxo, thioxo, cyano, nitro, optionally substituted aryl, optionallysubstituted aralkyl, optionally substituted aralkenyl, optionallysubstituted aralkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkylalkyl, optionally substituted heterocycloalkyl,optionally substituted heterocycloalkylalkyl, optionally substitutedheteroaryl, optionally substituted heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain, and where each of the abovesubstituents is unsubstituted unless otherwise indicated.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroaryloxy” refers to radical bonded through an oxygen atom of theformula —O— heteroaryl, where heteroaryl is as defined above.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

As used herein, “carboxylic acid bioisostere” refers to a functionalgroup or moiety that exhibits similar physical, biological and/orchemical properties as a carboxylic acid moiety. Examples of carboxylicacid bioisosteres include, but are not limited to,

and the like.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Incertain embodiments, the compounds presented herein exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution. “Optionally substituted” and “substituted orunsubstituted” and “unsubstituted or substituted” are usedinterchangeably herein.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the compoundsdescribed herein is intended to encompass any and all pharmaceuticallysuitable salt forms. Preferred pharmaceutically acceptable salts of thecompounds described herein are pharmaceutically acceptable acid additionsalts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and, aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are prepared by contacting the free base forms with asufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. In some embodiments, pharmaceutically acceptable baseaddition salts are formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supra.

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The term “about” when referring to a number or a numerical range meansthat the number or numerical range referred to is an approximationwithin experimental variability (or within statistical experimentalerror), and thus the number or numerical range varies between 1% and 15%of the stated number or numerical range.

The term “comprising” (and related terms such as “comprise” or“comprises” or “having” or “including”) is not intended to exclude thatwhich in other certain embodiments, for example, an embodiment of anycomposition of matter, composition, method, or process, or the like,described herein, “consist of” or “consist essentially of” the describedfeatures.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

As used herein, “treatment” or “treating” or “palliating” or“ameliorating” are used interchangeably herein. These terms refers to anapproach for obtaining beneficial or desired results including but notlimited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are administered to a patient atrisk of developing a particular disease, or to a patient reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease has been made.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the compoundsdescribed herein is intended to encompass any and all pharmaceuticallysuitable salt forms. Preferred pharmaceutically acceptable salts of thecompounds described herein are pharmaceutically acceptable acid additionsalts and pharmaceutically acceptable base addition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and, aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are prepared by contacting the free base forms with asufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. In some embodiments, pharmaceutically acceptable baseaddition salts are formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. See Berge et al., supra.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, are both administered to a patient simultaneously in theform of a single entity or dosage. The term “non-fixed combination”means that the active ingredients, are administered to a patient asseparate entities either simultaneously, concurrently or sequentiallywith no specific intervening time limits, wherein such administrationprovides effective levels of the two compounds in the body of thepatient. The latter also applies to cocktail therapy, e.g. theadministration of three or more active ingredients.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The term “activator” is used in this specification to denote anymolecular species that results in activation of the indicated receptor,regardless of whether the species itself binds to the receptor or ametabolite of the species binds to the receptor when the species isadministered topically. Thus, the activator can be a ligand of thereceptor or it can be an activator that is metabolized to the ligand ofthe receptor, i.e., a metabolite that is formed in tissue and is theactual ligand.

The term “antagonist” as used herein, refers to a small-molecule agentthat binds to a nuclear hormone receptor and subsequently decreases theagonist induced transcriptional activity of the nuclear hormonereceptor.

The term “agonist” as used herein, refers to a small-molecule agent thatbinds to a nuclear hormone receptor and subsequently increases nuclearhormone receptor transcriptional activity in the absence of a knownagonist.

The term “inverse agonist” as used herein, refers to a small-moleculeagent that binds to a nuclear hormone receptor and subsequentlydecreases the basal level of nuclear hormone receptor transcriptionalactivity that is present in the absence of a known agonist.

The term “modulate,” as used herein, means to interact with a targetprotein either directly or indirectly so as to alter the activity of thetarget protein, including, by way of example only, to inhibit theactivity of the target, or to limit or reduce the activity of thetarget.

As used herein, the term “modulator” refers to a compound that alters anactivity of a target. For example, a modulator can cause an increase ordecrease in the magnitude of a certain activity of a target compared tothe magnitude of the activity in the absence of the modulator. Incertain embodiments, a modulator is an inhibitor, which decreases themagnitude of one or more activities of a target. In certain embodiments,an inhibitor completely prevents one or more activities of a target.Compounds

FXR Modulators

Described herein are FXR modulatators, and pharmaceutical compositionsthat include such FXR modulatators, for use in the treatment ofdiseases, disorders or conditions that would benefit from FXRmodulation. In some embodiments is the administration of an FXRmodulator described herein to a mammal in the treatment of diseases,disorders or conditions that would benefit from FXR modulation. In someembodiments is the administration of an FXR modulator described hereinto a mammal in the treatment of diseases, disorders or conditions thatwould benefit from FXR modulation, wherein the FXR modulator is(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof.

In some embodiments is the administration of an FXR modulator describedherein to a mammal in the treatment of diseases, disorders or conditionsthat would benefit from FXR modulation, wherein the FXR modulator is(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof. Compound 1has the structure:

In some embodiments, a pharmaceutically acceptable salt of Compound 1 isa hydrochloride salt. In further embodiments, the pharmaceuticallyacceptable salt of Compound 1 is a mono-hydrochloride salt.

In some embodiments is the administration of an FXR modulator describedherein to a mammal in the treatment of diseases, disorders or conditionsthat would benefit from FXR modulation, wherein the FXR modulator is(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof. Compound 2has the structure:

In some embodiments, a pharmaceutically acceptable salt of Compound 2 isa hydrochloride salt. In further embodiments, the pharmaceuticallyacceptable salt of Compound 2 is a mono-hydrochloride salt.

In some embodiments is the administration of an FXR modulator describedherein to a mammal in the treatment of diseases, disorders or conditionsthat would benefit from FXR modulation, wherein the FXR modulator is(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof. Compound 3has the structure:

In some embodiments, a pharmaceutically acceptable salt of Compound 3 isa hydrochloride salt. In further embodiments, the pharmaceuticallyacceptable salt of Compound 3 is a mono-hydrochloride salt.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Solvates

In some embodiments, the compounds described herein exist as solvates.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein are conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein are conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran ormethanol. In addition, the compounds provided herein exist in unsolvatedas well as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that areincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N,¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, sulfur, fluorine and chloride,such as respectively. Compounds described herein, and pharmaceuticallyacceptable salts, esters, solvate, hydrates or derivatives thereof whichcontain the aforementioned isotopes and/or other isotopes of other atomsare within the scope of this invention. Certain isotopically-labeledcompounds, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i. e., ³H and carbon-14, i. e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavy isotopes such asdeuterium, i.e., ²H, produces certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements. Increased levels of deuteriumincorporation produce a detectable kinetic isotope effect (KIE) that mayaffect the pharmacokinetic, pharmacologic and/or toxicologic parametersof Compound 1, Compound 2, or Compound 3 in comparison to Compound 1,Compound 2, or Compound 3 having naturally occurring levels ofdeuterium. In some embodiments, the isotopically labeled compound, or apharmaceutically acceptable salt thereof, is prepared by any suitablemethod.

In some embodiments, at least one hydrogen in Compound 1 is replacedwith deuterium. In some embodiments of the methods described herein, atleast one hydrogen in Compound 1 is replaced with deuterium. In someembodiments of the pharmaceutical compositions described herein, atleast one hydrogen in Compound 1 is replaced with deuterium.

In some embodiments, at least one hydrogen in Compound 2 is replacedwith deuterium. In some embodiments of the methods described herein, atleast one hydrogen in Compound 2 is replaced with deuterium. In someembodiments of the pharmaceutical compositions described herein, atleast one hydrogen in Compound 2 is replaced with deuterium.

In some embodiments, at least one hydrogen in Compound 3 is replacedwith deuterium. In some embodiments of the methods described herein, atleast one hydrogen in Compound 3 is replaced with deuterium. In someembodiments of the pharmaceutical compositions described herein, atleast one hydrogen in Compound 3 is replaced with deuterium.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Methods of Treatment

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(I), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴ and R⁵ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and    optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵ together with the    carbon atom to which they are attached, form an optionally    substituted C₃-C₆cycloalkyl ring or an optionally substituted    C₂-C₇heterocycloalkyl ring;-   R⁶ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and    —C(O)N(R²⁷)R²⁸;-   R⁷ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally    substituted C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶,

-   R⁹ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R⁸ and R⁹    together with the carbon atoms to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring or an optionally    substituted heteroaryl ring;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl)-   R²⁷ and R²⁸ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the    nitrogen atom to which they are attached, form an optionally    substituted C₂-C₉heterocycloalkyl ring; or a pharmaceutically    acceptable salt, stereoisomer, or solvate thereof.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(II), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴ and R⁵ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and    optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵ together with the    carbon atom to which they are attached, form an optionally    substituted C₃-C₆cycloalkyl ring or an optionally substituted    C₂-C₇heterocycloalkyl ring;-   R⁶ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and    —C(O)N(R²⁷)R²⁸;-   R⁷ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally    substituted C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶,

-   R⁹ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R⁸ and R⁹    together with the carbon atoms to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring or an optionally    substituted heteroaryl ring;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²⁷ and R²⁸ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the    nitrogen atom to which they are attached, form an optionally    substituted C₂-C₉heterocycloalkyl ring; or a pharmaceutically    acceptable salt, stereoisomer, or solvate thereof.

In one embodiment, the FXR modulator is a compound of Formula (I) or(II) wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (I) or(II) wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (I) or (II)wherein R⁴ and R⁵ are each hydrogen. In another embodiment, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁴ and R⁵ areeach independently optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (I) or (II)wherein R⁴ and R⁵ are each methyl.

In another embodiment, the FXR modulator is a compound of Formula (I) or(II) wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (I) or(II) wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (I) or (II)wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (I) or (II) wherein R⁶ and R⁷ are each methyl. In anotherembodiment, the FXR modulator is a compound of Formula (I) or (II)wherein R⁶ and R⁷ are each hydrogen.

In another embodiment, the FXR modulator is a compound of Formula (I) or(II) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independentlyoptionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (I) or (II) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰is optionally substituted heteroaryl. In another embodiment, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (I) or (II) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl.

In another embodiment, the FXR modulator is a compound of Formula (I) or(II) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independentlyoptionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ isoptionally substituted aryl. In another embodiment, the FXR modulator isa compound of Formula (I) or (II) wherein R⁶ and R⁷ are hydrogen, R⁴ andR⁵ are independently optionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (I) or (II) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (I) or (II) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl.

In another embodiment, the FXR modulator is a compound of Formula (I) or(II) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independentlyoptionally substituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogenand R²² is optionally substituted aryl. In another embodiment, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (I) or (II) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (I) or (II) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) or (II) wherein R⁸ is selected from the group consistingof —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is —C(O)OR²⁵.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is —C(O)OR²⁵,and R²⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is independently selectedfrom the group consisting of hydrogen, and optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (I) or (II) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is hydrogen. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (I) or (II) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is unsubstituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (I) or (II) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is methyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (I) or (II) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (I) or (II) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is isopropyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is—C(O)N(R²⁵)R²⁶. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (I) or (II)wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected from thegroup consisting of hydrogen, and optionally substituted C₁-C₆alkyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (I) or (II) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ areeach independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (I) or (II) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (I) or (II) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵and R²⁶ are each independently unsubstituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (I) or (II) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (I) or (II) wherein R⁸ is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (I) or (II)wherein R⁸ is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (I) or (II) wherein R⁸ is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (I) or (II)wherein R⁸ is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (I) or (II) wherein R⁸ is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (I) or (II)wherein R⁸ is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁹ is selectedfrom the group consisting of hydrogen and optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (I) or (II) wherein R⁹ ishydrogen. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (I) or (II) wherein R⁹ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R⁹ is unsubstituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (I) or (II) wherein R⁹ is methyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ and R⁹together with the carbon atoms to which they are attached, form anoptionally substituted C₂-C₉heterocycloalkyl ring or an optionallysubstituted heteroaryl ring. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R⁸ and R⁹ together with the carbon atoms to whichthey are attached, form an optionally substituted C₂-C₉heterocycloalkylring. In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R⁸ and R⁹together with the carbon atoms to which they are attached, form anoptionally substituted heteroaryl ring.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R² is selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted heteroaryl, optionally substitutedC₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R² is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (I) or (II) wherein R² is optionally substituted C₁-C₆alkyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R² is methyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R² is ethyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (I) or (II) wherein R² is hydrogen.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R¹ is selectedfrom the group consisting of hydrogen, halogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted—(C₁-C₂alkylene)-(heteroaryl), and —OR¹⁰. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R¹ is hydrogen. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R¹ is halogen. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R¹ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (I) or (II) wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (I) or (II)wherein R¹ is optionally substituted C₂-C₆alkynyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (I) or (II) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (I) or (II) wherein R¹ is —OR¹⁰ andR¹⁰ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(I) or (II) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(III), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl;-   R⁹ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ is C₁-C₆alkyl;-   R³⁰ is halogen,

-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl;-   each R³² and R³³ are each independently selected from the group    consisting of hydrogen, halogen, and C₁-C₆alkyl;-   R³⁴ and R³⁵ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, and optionally substituted    C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with the nitrogen    atom to which they are attached, form an optionally substituted    C₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl    ring;-   n is 0, 1, 2, 3, or 4;-   r is 0, 1, 2, 3, or 4;-   t is 2, 3, or 4.

In one embodiment, the FXR modulator is a compound of Formula (III)wherein n is 0. In another embodiment, the FXR modulator is a compoundof Formula (III) wherein n is 1. In another embodiment, the FXRmodulator is a compound of Formula (III) wherein n is 2. In anotherembodiment, the FXR modulator is a compound of Formula (III) wherein nis 3. In another embodiment, the FXR modulator is a compound of Formula(III) wherein n is 4.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein n is 2 and each R³¹ is independently halogen, —OH, —CN, —NO₂,—NH₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionallysubstituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (III) wherein n is 2 and each R³¹is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (III)wherein n is 2 and each R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (III) wherein n is 2 and each R³¹ isF.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is F, n is 2, and each R³¹ is independently halogen, —OH,—CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (III) wherein R³⁰ is F, n is 2and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (III) wherein R³⁰ is F, n is 2 and each R³¹ is halogen. Inanother embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is F, n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment, the FXR modulator is a compound of Formula (III)wherein n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (III)wherein n is 1 and R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (III) wherein n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is F, n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (III) wherein R³⁰ is F, n is 1 and R³¹ is halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment, the FXR modulator is acompound of Formula (III) wherein R³⁰ is F, n is 1 and R³¹ is halogen.In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is F, n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (III)wherein r is 0. In another embodiment, the FXR modulator is a compoundof Formula (III) wherein r is 1. In another embodiment, the FXRmodulator is a compound of Formula (III) wherein r is 2. In anotherembodiment, the FXR modulator is a compound of Formula (III) wherein ris 3. In another embodiment, the FXR modulator is a compound of Formula(III) wherein r is 4. In one embodiment, the FXR modulator is a compoundof Formula (III) wherein each R³² and R³³ are hydrogen. In oneembodiment, the FXR modulator is a compound of Formula (III) wherein R³⁴and R³⁵ are each independently selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, and optionally substituted C₂-C₉heterocycloalkyl. Inanother embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁴ and R³⁵ are each independently selected from the groupconsisting of hydrogen, C₁-C₆alkyl, C₃-C₈cycloalkyl, andC₂-C₉heterocycloalkyl. In another embodiment, the FXR modulator is acompound of Formula (III) wherein R³⁴ and R³⁵ together with the nitrogenatom to which they are attached form an optionally substitutedC₂-C₉heterocycloalkyl ring. In another embodiment, the FXR modulator isa compound of Formula (III) wherein R³⁴ and R³⁵ together with thenitrogen atom to which they are attached form a pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, or methylpiperazinyl. In anotherembodiment, the FXR modulator is a compound of Formula (III) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forma morpholinyl. In another embodiment, the FXR modulator is a compound ofFormula (III) wherein R³⁴ and R³⁵ together with the nitrogen atom towhich they are attached form an optionally substituted heteroaryl ring.In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁴ and R³⁵ together with the nitrogen atom to which they areattached form an imidazolyl, pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

n is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (III) wherein R³⁰ is

n is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (III) wherein R³⁰ is

n is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (III) wherein R³⁰ is

n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (III) wherein R³⁰is

n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

n is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (III) wherein R³⁰ is

n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

and n is 0.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (III)wherein t is 2. In another embodiment, the FXR modulator is a compoundof Formula (III) wherein t is 3. In another embodiment, the FXRmodulator is a compound of Formula (III) wherein t is 4. In oneembodiment, the FXR modulator is a compound of Formula (III) whereineach R³² and R³³ are hydrogen. In one embodiment, the FXR modulator is acompound of Formula (III) wherein R³⁴ and R³⁵ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, and optionallysubstituted C₂-C₉heterocycloalkyl. In another embodiment, the FXRmodulator is a compound of Formula (III) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen,C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In anotherembodiment, the FXR modulator is a compound of Formula (III) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forman optionally substituted C₂-C₉heterocycloalkyl ring. In anotherembodiment, the FXR modulator is a compound of Formula (III) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forma pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, ormethylpiperazinyl. In another embodiment, the FXR modulator is acompound of Formula (III) wherein R³⁴ and R³⁵ together with the nitrogenatom to which they are attached form a morpholinyl. In anotherembodiment, the FXR modulator is a compound of Formula (III) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forman optionally substituted heteroaryl ring. In another embodiment, theFXR modulator is a compound of Formula (III) wherein R³⁴ and R³⁵together with the nitrogen atom to which they are attached form animidazolyl, pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

n is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (III) wherein R³⁰ is

n is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (III) wherein R³⁰ is

n is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (III) wherein R³⁰ is

n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (III) wherein R³⁰is

n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

n is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (III) wherein R³⁰ is

n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (III)wherein R³⁰ is

and n is 0.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (III) wherein R⁴ and R⁵ are eachmethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (III) wherein R⁴ and R⁵ are eachethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (III) wherein R¹ is hydrogen. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (III) wherein R¹ is halogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (III) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (III) wherein R¹ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (III) wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (III) wherein R¹is optionally substituted C₂-C₆alkynyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(III) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (III) wherein R¹ is —OR¹⁰ and R¹⁰ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (III) wherein R¹ is —OR¹⁰ andR¹⁰ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (III) whereinR²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (III) whereinR²⁵ is ethyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (III) wherein R²⁵ isisopropyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (III) wherein R⁹ is selected from thegroup consisting of hydrogen and optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (III) wherein R⁹ is hydrogen. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (III) wherein R⁹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (III) wherein R⁹ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (III) wherein R⁹is methyl.

In yet another embodiment, provided herein the FXR modulator is acompound having the structure of Formula (IIIa), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:

In yet another embodiment, provided herein the FXR modulator is acompound having the structure of Formula (IIIb), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:

In some embodiments, the FXR modulator is a compound of Formula (IIIa)or (IIIb) wherein R¹ is hydrogen. In some embodiments, the FXR modulatoris a compound of Formula (IIIa) or (IIIb) wherein R¹ is halogen. In someembodiments, the FXR modulator is a compound of Formula (IIIa) or (IIIb)wherein R¹ is optionally substituted C₁-C₆alkyl. In some embodiments,the FXR modulator is a compound of Formula (IIIa) or (IIIb) wherein R¹is optionally substituted C₂-C₆alkenyl. In some embodiments, the FXRmodulator is a compound of Formula (IIIa) or (IIIb) wherein R¹ isoptionally substituted C₂-C₆alkynyl. In some embodiments, the FXRmodulator is a compound of Formula (IIIa) or (IIIb) wherein R¹ is —OR¹⁰and R¹⁰ is hydrogen. In some embodiments, the FXR modulator is acompound of Formula (IIIa) or (IIIb) wherein R¹ is —OR¹⁰ and R¹⁰ isoptionally substituted C₁-C₆alkyl. In some embodiments, the FXRmodulator is a compound of Formula (IIIa) or (IIIb) wherein R¹ is —OR¹⁰and R¹⁰ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IIIa) or (IIIb)wherein R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IIIa) or (IIIb)wherein R²⁵ is ethyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IIIa) or (IIIb)wherein R²⁵ is isopropyl.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(IV), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl;-   R⁹ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ is C₁-C₆alkyl;-   R³⁰ is halogen,

-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl;-   each R³² and R³³ are each independently selected from the group    consisting of hydrogen, halogen, and C₁-C₆alkyl;-   R³⁴ and R³⁵ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, and optionally substituted    C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with the nitrogen    atom to which they are attached, form an optionally substituted    C₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl    ring;-   n is 0, 1, 2, 3, or 4;-   r is 0, 1, 2, 3, or 4;-   t is 2, 3, or 4.

In one embodiment, the FXR modulator is a compound of Formula (IV)wherein n is 0. In another embodiment, the FXR modulator is a compoundof Formula (IV) wherein n is 1. In another embodiment, the FXR modulatoris a compound of Formula (IV) wherein n is 2. In another embodiment, theFXR modulator is a compound of Formula (IV) wherein n is 3. In anotherembodiment, the FXR modulator is a compound of Formula (IV) wherein n is4.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein n is 2 and each R³¹ is independently halogen, —OH, —CN, —NO₂,—NH₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionallysubstituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (IV) wherein n is 2 and each R³¹is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (IV)wherein n is 2 and each R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (IV) wherein n is 2 and each R³¹ isF.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is F, n is 2, and each R³¹ is independently halogen, —OH,—CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (IV) wherein R³⁰ is F, n is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In another embodiment,the FXR modulator is a compound of Formula (IV) wherein R³⁰ is F, n is 2and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment, the FXR modulator is a compound of Formula (IV)wherein n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (IV)wherein n is 1 and R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (IV) wherein n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is F, n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (IV) wherein R³⁰ is F, n is 1 and R³¹ is halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment, the FXR modulator is acompound of Formula (IV) wherein R³⁰ is F, n is 1 and R³¹ is halogen. Inanother embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is F, n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (IV)wherein r is 0. In another embodiment, the FXR modulator is a compoundof Formula (IV) wherein r is 1. In another embodiment, the FXR modulatoris a compound of Formula (IV) wherein r is 2. In another embodiment, theFXR modulator is a compound of Formula (IV) wherein r is 3. In anotherembodiment, the FXR modulator is a compound of Formula (IV) wherein r is4. In one embodiment, the FXR modulator is a compound of Formula (IV)wherein each R³² and R³³ are hydrogen. In one embodiment, the FXRmodulator is a compound of Formula (IV) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, andoptionally substituted C₂-C₉heterocycloalkyl. In another embodiment, theFXR modulator is a compound of Formula (IV) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen,C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In anotherembodiment, the FXR modulator is a compound of Formula (IV) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forman optionally substituted C₂-C₉heterocycloalkyl ring. In anotherembodiment, the FXR modulator is a compound of Formula (IV) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forma pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, ormethylpiperazinyl. In another embodiment, the FXR modulator is acompound of Formula (IV) wherein R³⁴ and R³⁵ together with the nitrogenatom to which they are attached form a morpholinyl. In anotherembodiment, the FXR modulator is a compound of Formula (IV) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forman optionally substituted heteroaryl ring. In another embodiment, theFXR modulator is a compound of Formula (IV) wherein R³⁴ and R³⁵ togetherwith the nitrogen atom to which they are attached form an imidazolyl,pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

n is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (IV) wherein R³⁰ is

n is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (IV) wherein R³⁰ is

n is 2 and each R³¹ is halogen. In another embodiment FXR modulator is acompound of Formula (IV) wherein R³⁰ is

n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (IV) wherein R³⁰is

n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

n is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (IV) wherein R³⁰ is

n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

and n is 0.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (IV)wherein t is 2. In another embodiment, the FXR modulator is a compoundof Formula (IV) wherein t is 3. In another embodiment, the FXR modulatoris a compound of Formula (IV) wherein t is 4. In one embodiment, the FXRmodulator is a compound of Formula (IV) wherein each R³² and R³³ arehydrogen. In one embodiment, the FXR modulator is a compound of Formula(IV) wherein R³⁴ and R³⁵ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, and optionally substitutedC₂-C₉heterocycloalkyl. In another embodiment, the FXR modulator is acompound of Formula (IV) wherein R³⁴ and R³⁵ are each independentlyselected from the group consisting of hydrogen, C₁-C₆alkyl,C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In another embodiment, theFXR modulator is a compound of Formula (IV) wherein R³⁴ and R³⁵ togetherwith the nitrogen atom to which they are attached form an optionallysubstituted C₂-C₉heterocycloalkyl ring. In another embodiment, the FXRmodulator is a compound of Formula (IV) wherein R³⁴ and R³⁵ togetherwith the nitrogen atom to which they are attached form a pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, or methylpiperazinyl. In anotherembodiment, the FXR modulator is a compound of Formula (IV) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forma morpholinyl. In another embodiment, the FXR modulator is a compound ofFormula (IV) wherein R³⁴ and R³⁵ together with the nitrogen atom towhich they are attached form an optionally substituted heteroaryl ring.In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁴ and R³⁵ together with the nitrogen atom to which they areattached form an imidazolyl, pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

n is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (IV) wherein R³⁰ is

n is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (IV) wherein R³⁰ is

n is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (IV) wherein R³⁰ is

n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (IV) wherein R³⁰is

n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

n is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (IV) wherein R³⁰ is

n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (IV)wherein R³⁰ is

and n is 0.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IV) wherein R⁴ and R⁵ are eachmethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (IV) wherein R⁴ and R⁵ are eachethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (IV) wherein R¹ is hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (IV) wherein R¹ is halogen. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (IV) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (IV) wherein R¹ is methyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IV) wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IV) wherein R¹is optionally substituted C₂-C₆alkynyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(IV) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (IV) wherein R¹ is —OR¹⁰ and R¹⁰ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (IV) wherein R¹ is —OR¹⁰ andR¹⁰ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IV) wherein R²⁵is methyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (IV) wherein R²⁵ is ethyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IV) wherein R²⁵ is isopropyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IV) wherein R⁹ is selected from thegroup consisting of hydrogen and optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (IV) wherein R⁹ is hydrogen. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (IV) wherein R⁹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (IV) wherein R⁹ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IV) wherein R⁹is methyl.

In yet another embodiment, provided herein the FXR modulator is acompound having the structure of Formula (IVa), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:

In yet another embodiment, provided herein the FXR modulator is acompound having the structure of Formula (IVb), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:

In some embodiments, the FXR modulator is a compound of Formula (IVa) or(IVb) wherein R¹ is hydrogen. In some embodiments, the FXR modulator isa compound of Formula (IVa) or (IVb) wherein R¹ is halogen. In someembodiments, the FXR modulator is a compound of Formula (IVa) or (IVb)wherein R¹ is optionally substituted C₁-C₆alkyl. In some embodiments,the FXR modulator is a compound of Formula (IVa) or (IVb) wherein R¹ isoptionally substituted C₂-C₆alkenyl. In some embodiments, the FXRmodulator is a compound of Formula (IVa) or (IVb) wherein R¹ isoptionally substituted C₂-C₆alkynyl. In some embodiments, the FXRmodulator is a compound of Formula (IVa) or (IVb) wherein R¹ is —OR¹⁰and R¹⁰ is hydrogen. In some embodiments, the FXR modulator is acompound of Formula (IVa) or (IVb) wherein R¹ is —OR¹⁰ and R¹⁰ isoptionally substituted C₁-C₆alkyl. In some embodiments, the FXRmodulator is a compound of Formula (IVa) or (IVb) wherein R¹ is —OR¹⁰and R¹⁰ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IVa) or (IVb)wherein R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IVa) or (IVb)wherein R²⁵ is ethyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IVa) or (IVb)wherein R²⁵ is isopropyl.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(V), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl;-   R⁹ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, and optionally substituted C₁-C₆alkyl;-   R³⁰ is halogen,

-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl;-   each R³² and R³³ are each independently selected from the group    consisting of hydrogen, halogen, and C₁-C₆alkyl;-   R³⁴ and R³⁵ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, and optionally substituted    C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with the nitrogen    atom to which they are attached, form an optionally substituted    C₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl    ring;-   n is 0, 1, 2, 3, or 4;-   r is 0, 1, 2, 3, or 4;-   t is 2, 3, or 4.

In one embodiment, the FXR modulator is a compound of Formula (V)wherein n is 0. In another embodiment, the FXR modulator is a compoundof Formula (V) wherein n is 1. In another embodiment, the FXR modulatoris a compound of Formula (V) wherein n is 2. In another embodiment, theFXR modulator is a compound of Formula (V) wherein n is 3. In anotherembodiment, the FXR modulator is a compound of Formula (V) wherein n is4.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein n is 2 and each R³¹ is independently halogen, —OH, —CN, —NO₂,—NH₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionallysubstituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (V) wherein n is 2 and each R³¹is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (V)wherein n is 2 and each R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (V) wherein n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is F, n is 2, and each R³¹ is independently halogen, —OH,—CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (V) wherein R³⁰ is F, n is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In another embodiment,the FXR modulator is a compound of Formula (V) wherein R³⁰ is F, n is 2and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment, the FXR modulator is a compound of Formula (V)wherein n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (V)wherein n is 1 and R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (V) wherein n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is F, n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (V) wherein R³⁰ is F, n is 1 and R³¹ is halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment, the FXR modulator is acompound of Formula (V) wherein R³⁰ is F, n is 1 and R³¹ is halogen. Inanother embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is F, n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (V)wherein r is 0. In another embodiment, the FXR modulator is a compoundof Formula (V) wherein r is 1. In another embodiment, the FXR modulatoris a compound of Formula (V) wherein r is 2. In another embodiment, theFXR modulator is a compound of Formula (V) wherein r is 3. In anotherembodiment, the FXR modulator is a compound of Formula (V) wherein r is4. In one embodiment, the FXR modulator is a compound of Formula (V)wherein each R³² and R³³ are hydrogen. In one embodiment, the FXRmodulator is a compound of Formula (V) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, andoptionally substituted C₂-C₉heterocycloalkyl. In another embodiment, theFXR modulator is a compound of Formula (V) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen,C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In anotherembodiment, the FXR modulator is a compound of Formula (V) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forman optionally substituted C₂-C₉heterocycloalkyl ring. In anotherembodiment, the FXR modulator is a compound of Formula (V) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forma pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, ormethylpiperazinyl. In another embodiment, the FXR modulator is acompound of Formula (V) wherein R³⁴ and R³⁵ together with the nitrogenatom to which they are attached form a morpholinyl. In anotherembodiment, the FXR modulator is a compound of Formula (V) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forman optionally substituted heteroaryl ring. In another embodiment, theFXR modulator is a compound of Formula (V) wherein R³⁴ and R³⁵ togetherwith the nitrogen atom to which they are attached form an imidazolyl,pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

n is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (V) wherein R³⁰ is

n is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (V) wherein R³⁰ is

n is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (V) wherein R³⁰ is

n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (V) wherein R³⁰is

n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

n is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (V) wherein R³⁰ is

n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

and n is 0.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (V)wherein t is 2. In another embodiment, the FXR modulator is a compoundof Formula (V) wherein t is 3. In another embodiment, the FXR modulatoris a compound of Formula (V) wherein t is 4. In one embodiment, the FXRmodulator is a compound of Formula (V) wherein each R³² and R³³ arehydrogen. In one embodiment, the FXR modulator is a compound of Formula(V) wherein R³⁴ and R³⁵ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, and optionally substitutedC₂-C₉heterocycloalkyl. In another embodiment, the FXR modulator is acompound of Formula (V) wherein R³⁴ and R³⁵ are each independentlyselected from the group consisting of hydrogen, C₁-C₆alkyl,C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In another embodiment, theFXR modulator is a compound of Formula (V) wherein R³⁴ and R³⁵ togetherwith the nitrogen atom to which they are attached form an optionallysubstituted C₂-C₉heterocycloalkyl ring. In another embodiment, the FXRmodulator is a compound of Formula (V) wherein R³⁴ and R³⁵ together withthe nitrogen atom to which they are attached form a pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, or methylpiperazinyl. In anotherembodiment, the FXR modulator is a compound of Formula (V) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forma morpholinyl. In another embodiment, the FXR modulator is a compound ofFormula (V) wherein R³⁴ and R³⁵ together with the nitrogen atom to whichthey are attached form an optionally substituted heteroaryl ring. Inanother embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁴ and R³⁵ together with the nitrogen atom to which they areattached form an imidazolyl, pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

n is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (V) wherein R³⁰ is

n is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (V) wherein R³⁰ is

n is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (V) wherein R³⁰ is

n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (V) wherein R³⁰is

n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

n is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (V) wherein R³⁰ is

n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (V)wherein R³⁰ is

and n is 0.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (V) wherein R⁴ and R⁵ are eachmethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (V) wherein R⁴ and R⁵ are eachethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (V) wherein R¹ is hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (V) wherein R¹ is halogen. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (V) wherein R¹ is optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (V) wherein R¹ is methyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (V) wherein R¹ is optionally substitutedC₂-C₆alkenyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (V) wherein R¹ is optionallysubstituted C₂-C₆alkynyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (V) wherein R¹is —OR¹⁰ and R¹⁰ is hydrogen. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(V) wherein R¹ is —OR¹⁰ and R¹⁰ is optionally substituted C₁-C₆alkyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (V) wherein R¹ is —OR¹⁰ and R¹⁰ ismethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (V) wherein R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (V) wherein R²⁵ is hydrogen andR²⁶ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(V) wherein R²⁵ is hydrogen and R²⁶ is methyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (V) wherein R²⁵ is hydrogen and R²⁶ is ethyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (V) wherein R²⁵ is hydrogen and R²⁶ is isopropyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (V) wherein R²⁵ and R²⁶ are eachoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(V) wherein R²⁵ and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(V) wherein R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (V) wherein R⁹ is selected from thegroup consisting of hydrogen and optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (V) wherein R⁹ is hydrogen. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (V) wherein R⁹ is optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (V) wherein R⁹ is unsubstitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (V) wherein R⁹ is methyl.

In yet another embodiment, provided herein the FXR modulator is acompound having the structure of Formula (Va), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:

In yet another embodiment, provided herein the FXR modulator is acompound having the structure of Formula (Vb), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:

In some embodiments, the FXR modulator is a compound of Formula (Va) or(Vb) wherein R¹ is hydrogen. In some embodiments, the FXR modulator is acompound of Formula (Va) or (Vb) wherein R¹ is halogen. In someembodiments, the FXR modulator is a compound of Formula (Va) or (Vb)wherein R¹ is optionally substituted C₁-C₆alkyl. In some embodiments,the FXR modulator is a compound of Formula (Va) or (Vb) wherein R¹ isoptionally substituted C₂-C₆alkenyl. In some embodiments, the FXRmodulator is a compound of Formula (Va) or (Vb) wherein R¹ is optionallysubstituted C₂-C₆alkynyl. In some embodiments, the FXR modulator is acompound of Formula (Va) or (Vb) wherein R¹ is —OR¹⁰ and R¹⁰ ishydrogen. In some embodiments, the FXR modulator is a compound ofFormula (Va) or (Vb) wherein R¹ is —OR¹⁰ and R¹⁰ is optionallysubstituted C₁-C₆alkyl. In some embodiments, the FXR modulator is acompound of Formula (Va) or (Vb) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (Va) or (Vb) wherein R²⁵ and R²⁶ arehydrogen. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (Va) or (Vb) wherein R²⁵ ishydrogen and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (Va) or (Vb) wherein R²⁵ is hydrogen and R²⁶ ismethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (Va) or (Vb) wherein R²⁵ ishydrogen and R²⁶ is ethyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (Va) or (Vb)wherein R²⁵ is hydrogen and R²⁶ is isopropyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (Va) or (Vb) wherein R²⁵ and R²⁶ are each optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (Va) or (Vb) wherein R²⁵ andR²⁶ are methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (Va) or (Vb)wherein R²⁵ and R²⁶ are ethyl.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(VI), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R⁴ and R⁵ are each independently optionally substituted C₁-C₆alkyl;-   R⁹ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, and optionally substituted C₁-C₆alkyl;-   R³⁰ is halogen,

-   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionally    substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,    optionally substituted C₁-C₆alkylamine, optionally substituted    C₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl,    or heteroaryl;-   each R³² and R³³ are each independently selected from the group    consisting of hydrogen, halogen, and C₁-C₆alkyl;-   R³⁴ and R³⁵ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, and optionally substituted    C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with the nitrogen    atom to which they are attached, form an optionally substituted    C₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl    ring;-   n is 0, 1, 2, 3, or 4;-   r is 0, 1, 2, 3, or 4;-   t is 2, 3, or 4.

In one embodiment, the FXR modulator is a compound of Formula (VI)wherein n is 0. In another embodiment, the FXR modulator is a compoundof Formula (VI) wherein n is 1. In another embodiment, the FXR modulatoris a compound of Formula (VI) wherein n is 2. In another embodiment, theFXR modulator is a compound of Formula (VI) wherein n is 3. In anotherembodiment, the FXR modulator is a compound of Formula (VI) wherein n is4.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein n is 2 and each R³¹ is independently halogen, —OH, —CN, —NO₂,—NH₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionallysubstituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (VI) wherein n is 2 and each R³¹is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (VI)wherein n is 2 and each R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (VI) wherein n is 2 and each R³¹ isF.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is F, n is 2, and each R³¹ is independently halogen, —OH,—CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (VI) wherein R³⁰ is F, n is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is F, n is 2 and each R³¹ is halogen. In another embodiment,the FXR modulator is a compound of Formula (VI) wherein R³⁰ is F, n is 2and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment, the FXR modulator is a compound of Formula (VI)wherein n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (VI)wherein n is 1 and R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (VI) wherein n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is F, n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VI) wherein R³⁰ is F, n is 1 and R³¹ is halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment, the FXR modulator is acompound of Formula (VI) wherein R³⁰ is F, n is 1 and R³¹ is halogen. Inanother embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is F, n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (VI)wherein r is 0. In another embodiment, the FXR modulator is a compoundof Formula (VI) wherein r is 1. In another embodiment, the FXR modulatoris a compound of Formula (VI) wherein r is 2. In another embodiment, theFXR modulator is a compound of Formula (VI) wherein r is 3. In anotherembodiment, the FXR modulator is a compound of Formula (VI) wherein r is4. In one embodiment, the FXR modulator is a compound of Formula (VI)wherein each R³² and R³³ are hydrogen. In one embodiment, the FXRmodulator is a compound of Formula (VI) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, andoptionally substituted C₂-C₉heterocycloalkyl. In another embodiment, theFXR modulator is a compound of Formula (VI) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen,C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In anotherembodiment, the FXR modulator is a compound of Formula (VI) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forman optionally substituted C₂-C₉heterocycloalkyl ring. In anotherembodiment, the FXR modulator is a compound of Formula (VI) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forma pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, ormethylpiperazinyl. In another embodiment, the FXR modulator is acompound of Formula (VI) wherein R³⁴ and R³⁵ together with the nitrogenatom to which they are attached form a morpholinyl. In anotherembodiment, the FXR modulator is a compound of Formula (VI) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forman optionally substituted heteroaryl ring. In another embodiment, theFXR modulator is a compound of Formula (VI) wherein R³⁴ and R³⁵ togetherwith the nitrogen atom to which they are attached form an imidazolyl,pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

n is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VI) wherein R³⁰ is

n is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VI) wherein R³⁰ is

n is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (VI) wherein R³⁰ is

n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (VI) wherein R³⁰is

n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

n is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (VI) wherein R³⁰ is

n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

and n is 0.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (VI)wherein t is 2. In another embodiment, the FXR modulator is a compoundof Formula (VI) wherein t is 3. In another embodiment, the FXR modulatoris a compound of Formula (VI) wherein t is 4. In one embodiment, the FXRmodulator is a compound of Formula (VI) wherein each R³² and R³³ arehydrogen. In one embodiment, the FXR modulator is a compound of Formula(VI) wherein R³⁴ and R³⁵ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, and optionally substitutedC₂-C₉heterocycloalkyl. In another embodiment, the FXR modulator is acompound of Formula (VI) wherein R³⁴ and R³⁵ are each independentlyselected from the group consisting of hydrogen, C₁-C₆alkyl,C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In another embodiment, theFXR modulator is a compound of Formula (VI) wherein R³⁴ and R³⁵ togetherwith the nitrogen atom to which they are attached form an optionallysubstituted C₂-C₉heterocycloalkyl ring. In another embodiment, the FXRmodulator is a compound of Formula (VI) wherein R³⁴ and R³⁵ togetherwith the nitrogen atom to which they are attached form a pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, or methylpiperazinyl. In anotherembodiment, the FXR modulator is a compound of Formula (VI) wherein R³⁴and R³⁵ together with the nitrogen atom to which they are attached forma morpholinyl. In another embodiment, the FXR modulator is a compound ofFormula (VI) wherein R³⁴ and R³⁵ together with the nitrogen atom towhich they are attached form an optionally substituted heteroaryl ring.In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁴ and R³⁵ together with the nitrogen atom to which they areattached form an imidazolyl, pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

n is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VI) wherein R³⁰ is

n is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VI) wherein R³⁰ is

n is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (VI) wherein R³⁰ is

n is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

n is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (VI) wherein R³⁰is

n is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

n is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (VI) wherein R³⁰ is

n is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VI)wherein R³⁰ is

and n is 0.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VI) wherein R⁴ and R⁵ are eachmethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (VI) wherein R⁴ and R⁵ are eachethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (VI) wherein R¹ is hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VI) wherein R¹ is halogen. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VI) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VI) wherein R¹ is methyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VI) wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VI) wherein R¹is optionally substituted C₂-C₆alkynyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VI) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VI) wherein R¹ is —OR¹⁰ and R¹⁰ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VI) wherein R¹ is —OR¹⁰ andR¹⁰ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VI) wherein R²⁵and R²⁶ are hydrogen. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VI) wherein R²⁵is hydrogen and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VI) wherein R²⁵ is hydrogen and R²⁶ is methyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VI) wherein R²⁵ is hydrogen and R²⁶ is ethyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VI) wherein R²⁵ is hydrogen and R²⁶is isopropyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VI) wherein R²⁵ and R²⁶ areeach optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VI) wherein R²⁵ and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VI) wherein R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VI) wherein R⁹ is selected from thegroup consisting of hydrogen and optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VI) wherein R⁹ is hydrogen. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VI) wherein R⁹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (V VI wherein R⁹ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VI) wherein R⁹is methyl.

In yet another embodiment, provided herein the FXR modulator is acompound having the structure of Formula (VIa), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:

In yet another embodiment, provided herein the FXR modulator is acompound having the structure of Formula (VIb), or a pharmaceuticallyacceptable salt, stereoisomer, or solvate thereof:

In some embodiments, the FXR modulator is a compound of Formula (VIa) or(VIb) wherein R¹ is hydrogen. In some embodiments, the FXR modulator isa compound of Formula (VIa) or (VIb) wherein R¹ is halogen. In someembodiments, the FXR modulator is a compound of Formula (VIa) or (VIb)wherein R¹ is optionally substituted C₁-C₆alkyl. In some embodiments,the FXR modulator is a compound of Formula (VIa) or (VIb) wherein R¹ isoptionally substituted C₂-C₆alkenyl. In some embodiments, the FXRmodulator is a compound of Formula (VIa) wherein R¹ is optionallysubstituted C₂-C₆alkynyl. In some embodiments, the FXR modulator is acompound of Formula (VIa) or (VIb) wherein R¹ is —OR¹⁰ and R¹⁰ ishydrogen. In some embodiments, the FXR modulator is a compound ofFormula (VIa) or (VIb) wherein R¹ is —OR¹⁰ and R¹⁰ is optionallysubstituted C₁-C₆alkyl. In some embodiments, the FXR modulator is acompound of Formula (VIa) or (VIb) wherein R¹ is —OR¹⁰ and R¹⁰ ismethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (VIa) or (VIb) wherein R²⁵ andR²⁶ are hydrogen. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIa) or (VIb)wherein R²⁵ is hydrogen and R²⁶ is optionally substituted C₁-C₆alkyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIa) or (VIb) wherein R²⁵ ishydrogen and R²⁶ is methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIa) or (VIb) wherein R²⁵ is hydrogen and R²⁶ is ethyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIa) or (VIb) wherein R²⁵ is hydrogen and R²⁶ isisopropyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VIa) or (VIb) wherein R²⁵and R²⁶ are each optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIa) or (VIb) wherein R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIa) or (VIb) wherein R²⁵ and R²⁶ are ethyl.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(VII), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

-   -    or R¹ and R² together with the carbon atoms to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring or an optionally substituted heteroaryl ring;    -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇cycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ together with the carbon atoms to which they are        attached, form an optionally substituted nitrogen containing        6-membered heteroaryl ring;    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R²¹ and        R²² together with the nitrogen atom to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring.

In one embodiment, the FXR modulator is a compound of Formula (VII)wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (VII)wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (VII) wherein R⁴and R⁵ are each hydrogen. In another embodiment, the FXR modulator is acompound of Formula (VII) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment, the FXRmodulator is a compound of Formula (VII) wherein R⁴ and R⁵ are eachmethyl. In another embodiment, the FXR modulator is a compound ofFormula (VII) wherein R⁴ and R⁵ form an optionally substitutedC₃-C₆cycloalkyl ring or an optionally substituted C₂-C₇heterocycloalkylring. In some embodiments, the FXR modulator is a compound of Formula(VII) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments, the FXR modulator is a compound of Formula(VII) wherein R⁴ and R⁵ form an optionally substitutedC₂-C₇heterocycloalkyl ring.

In another embodiment, the FXR modulator is a compound of Formula (VII)wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (VII)wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (VII) wherein R⁶and R⁷ are each independently optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (VII)wherein R⁶ and R⁷ are each methyl. In another embodiment, the FXRmodulator is a compound of Formula (VII) wherein R⁶ and R⁷ are eachhydrogen.

In another embodiment, the FXR modulator is a compound of Formula (VII)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (VII) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰is optionally substituted heteroaryl. In another embodiment, the FXRmodulator is a compound of Formula (VII) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment, the FXR modulator is a compound of Formula(VII) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is—C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl.

In another embodiment, the FXR modulator is a compound of Formula (VII)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (VII) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, andR²⁰ is optionally substituted heteroaryl. In another embodiment, the FXRmodulator is a compound of Formula (VII) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substitutedaryl. In another embodiment, the FXR modulator is a compound of Formula(VII) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is—S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl.

In another embodiment, the FXR modulator is a compound of Formula (VII)wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted aryl. In another embodiment, the FXR modulator isa compound of Formula (VII) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵are independently optionally substituted C₁-C₆alkyl, R³ is—C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VII) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment, the FXR modulator is a compound of Formula(VII) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is—C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedheteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (I) wherein R² is selected from the group consisting of —CN,—C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is —C(O)OR²⁵. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VII) wherein R² is —C(O)OR²⁵, and R²⁵ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VII) wherein R² is —C(O)OR²⁵, and R²⁵ is independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is —C(O)OR²⁵, andR²⁵ is hydrogen. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VII) wherein R²is —C(O)OR²⁵, and R²⁵ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VII) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VII) wherein R²is —C(O)OR²⁵, and R²⁵ is methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VII) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is —C(O)N(R²⁵)R²⁶.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is —C(O)N(R²⁵)R²⁶,and R²⁵ and R²⁶ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ andR²⁶ are each independently optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VII) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently unsubstituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (VII) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ aremethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (VII) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VII) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VII) wherein R²is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VII) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VII) wherein R²is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VII) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VII) wherein R²is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R¹ is selected from thegroup consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R¹ is hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VII) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VII) wherein R¹ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VII) wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R¹ and R² together withthe carbon atoms to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring or an optionally substitutedheteroaryl ring. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VII) wherein R¹and R² together with the carbon atoms to which they are attached, forman optionally substituted C₂-C₉heterocycloalkyl ring. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VII) wherein R¹ and R² together with the carbonatoms to which they are attached, form an optionally substitutedheteroaryl ring.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R⁸ is selected from thegroup consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedheteroaryl, optionally substituted C₂-C₉heterocycloalkyl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VII) wherein R⁸ is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (VII) wherein R⁸ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VII) wherein R⁸ is methyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VII) wherein R⁸ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VII) wherein R⁸ is ethyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VII) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VII) wherein R⁸is hydrogen.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIIa), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIIb), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIIc), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIId), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIIe), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIIf), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIIg), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIIh), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIIi), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VII) has the structure ofFormula (VIIj), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In some embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein n is 0. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein n is 1. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein n is 2. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein n is 1 and R¹¹ is selected from the groupconsisting of halogen, —CN, amino, alkylamino, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIa)-(VIIj) wherein n is 1 and R¹¹ is selectedfrom the group consisting of halogen, —CN, C₁-C₆alkyl, and C₁-C₆alkoxy.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein n is 1 and R¹¹is halogen.

In another embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. In anotherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIa)-(VIIj) wherein R⁶ and R⁷ are hydrogen, R⁴ andR⁵ are independently optionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰,and R²⁰ is optionally substituted heteroaryl. In another embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIa)-(VIIj) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIIa)-(VIIj) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedheteroaryl.

In another embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. In anotherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIa)-(VIIj) wherein R⁶ and R⁷ are hydrogen, R⁴ andR⁵ are independently optionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl. In another embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIa)-(VIIj) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted aryl. Inanother embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIIa)-(VIIj) wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substitutedheteroaryl.

In another embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In another embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedheteroaryl. In another embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (VIIa)-(VIIj) wherein R⁶ and R⁷are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted aryl. In another embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIa)-(VIIj) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted heteroaryl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is selectedfrom the group consisting of —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is—C(O)OR²⁵. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VIIa)-(VIIj) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein R² is —C(O)OR²⁵, and R²⁵ is independently selectedfrom the group consisting of hydrogen, and optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VIIa)-(VIIj) wherein R² is—C(O)OR²⁵, and R²⁵ is hydrogen. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein R² is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VIIa)-(VIIj) wherein R² is—C(O)OR²⁵, and R²⁵ is unsubstituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIa)-(VIIj) wherein R² is —C(O)OR²⁵, and R²⁵ is methyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIIa)-(VIIj) wherein R² is —C(O)OR²⁵, and R²⁵is ethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (VIIa)-(VIIj) wherein R² is—C(O)OR²⁵, and R²⁵ is isopropyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is—C(O)N(R²⁵)R²⁶. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIa)-(VIIj)wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected from thegroup consisting of hydrogen, and optionally substituted C₁-C₆alkyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIa)-(VIIj) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ areeach independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIa)-(VIIj) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIa)-(VIIj) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵and R²⁶ are each independently unsubstituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIa)-(VIIj) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIa)-(VIIj) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIa)-(VIIj)wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIa)-(VIIj) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIa)-(VIIj)wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIa)-(VIIj) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIa)-(VIIj)wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R¹ is selectedfrom the group consisting of hydrogen and optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VIIa)-(VIIj) wherein R¹ ishydrogen. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (VIIa)-(VIIj) wherein R¹ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein R¹ is unsubstituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIa)-(VIIj) wherein R¹ is methyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R⁸ is selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted heteroaryl, optionally substitutedC₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein R⁸ is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIa)-(VIIj) wherein R⁸ is optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R⁸ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIa)-(VIIj) wherein R⁸ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein R⁸ is methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIa)-(VIIj) wherein R⁸ is hydrogen.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(VIII), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

-   -    or R¹ and R² together with the carbon atoms to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring or an optionally substituted heteroaryl ring;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);

R⁹ and R¹⁰ together with the carbon atoms to which they are attached,form an optionally substituted nitrogen containing 6-membered heteroarylring;

-   -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;

R³⁰ is halogen, each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl;

-   -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring or an optionally        substituted heteroaryl ring;    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In one embodiment, the FXR modulator is a compound of Formula (VIII)wherein p is 0. In another embodiment, the FXR modulator is a compoundof Formula (VIII) wherein p is 1. In another embodiment, the FXRmodulator is a compound of Formula (VIII) wherein p is 2. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) wherein pis 3. In another embodiment, the FXR modulator is a compound of Formula(VIII) wherein p is 4.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein p is 2 and each R³¹ is independently halogen, —OH, —CN, —NO₂,—NH₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionallysubstituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (VIII) wherein p is 2 and eachR³¹ is independently halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (VIII)wherein p is 2 and each R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (VIII) wherein p is 2 and each R³¹ isF.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is F, p is 2, and each R³¹ is independently halogen, —OH,—CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (VIII) wherein R³⁰ is F, p is 2and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VIII) wherein R³⁰ is F, p is 2 and each R³¹ is halogen. Inanother embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is F, p is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Inanother embodiment, the FXR modulator is a compound of Formula (VIII)wherein p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein p is 1 and R³¹ is halogen. In another embodiment, the FXRmodulator is a compound of Formula (VIII) wherein p is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is F, p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VIII) wherein R³⁰ is F, p is 1 and R³¹ is halogen, oroptionally substituted C₁-C₆alkyl. In another embodiment, the FXRmodulator is a compound of Formula (VIII) wherein R³⁰ is F, p is 1 andR³¹ is halogen. In another embodiment, the FXR modulator is a compoundof Formula (VIII) wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (VIII)wherein r is 0. In another embodiment, the FXR modulator is a compoundof Formula (VIII) wherein r is 1. In another embodiment, the FXRmodulator is a compound of Formula (VIII) wherein r is 2. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) wherein ris 3. In another embodiment, the FXR modulator is a compound of Formula(VIII) wherein r is 4. In one embodiment, the FXR modulator is acompound of Formula (VIII) wherein each R³² and R³³ are hydrogen. In oneembodiment, the FXR modulator is a compound of Formula (VIII) whereinR³⁴ and R³⁵ are each independently selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, and optionally substituted C₂-C₉heterocycloalkyl. Inanother embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁴ and R³⁵ are each independently selected from the groupconsisting of hydrogen, C₁-C₆alkyl, C₃-C₈cycloalkyl, andC₂-C₉heterocycloalkyl. In another embodiment, the FXR modulator is acompound of Formula (VIII) wherein R³⁴ and R³⁵ together with thenitrogen atom to which they are attached form an optionally substitutedC₂-C₉heterocycloalkyl ring. In another embodiment, the FXR modulator isa compound of Formula (VIII) wherein R³⁴ and R³⁵ together with thenitrogen atom to which they are attached form a pyrrolidinyl,piperidinyl, morpholinyl, piperazinyl, or methylpiperazinyl. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) whereinR³⁴ and R³⁵ together with the nitrogen atom to which they are attachedform a morpholinyl. In another embodiment, the FXR modulator is acompound of Formula (VIII) wherein R³⁴ and R³⁵ together with thenitrogen atom to which they are attached form an optionally substitutedheteroaryl ring. In another embodiment, the FXR modulator is a compoundof Formula (VIII) wherein R³⁴ and R³⁵ together with the nitrogen atom towhich they are attached form an imidazolyl, pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VIII) wherein R³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VIII) wherein R³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (VIII) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) whereinR³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (VIII) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

and p is 0.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula (VIII)wherein t is 2. In another embodiment, the FXR modulator is a compoundof Formula (VIII) wherein t is 3. In another embodiment, the FXRmodulator is a compound of Formula (VIII) wherein t is 4. In oneembodiment, the FXR modulator is a compound of Formula (VIII) whereineach R³² and R³³ are hydrogen. In one embodiment, the FXR modulator is acompound of Formula (VIII) wherein R³⁴ and R³⁵ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, and optionallysubstituted C₂-C₉heterocycloalkyl. In another embodiment, the FXRmodulator is a compound of Formula (VIII) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen,C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) whereinR³⁴ and R³⁵ together with the nitrogen atom to which they are attachedform an optionally substituted C₂-C₉heterocycloalkyl ring. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) whereinR³⁴ and R³⁵ together with the nitrogen atom to which they are attachedform a pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, ormethylpiperazinyl. In another embodiment, the FXR modulator is acompound of Formula (VIII) wherein R³⁴ and R³⁵ together with thenitrogen atom to which they are attached form a morpholinyl. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) whereinR³⁴ and R³⁵ together with the nitrogen atom to which they are attachedform an optionally substituted heteroaryl ring. In another embodiment,the FXR modulator is a compound of Formula (VIII) wherein R³⁴ and R³⁵together with the nitrogen atom to which they are attached form animidazolyl, pyrazolyl, or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VIII) wherein R³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VIII) wherein R³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (VIII) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) whereinR³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (VIII) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R³⁰ is

and p is 0.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) wherein R⁴and R⁵ are each hydrogen. In another embodiment, the FXR modulator is acompound of Formula (VIII) wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In another embodiment, the FXRmodulator is a compound of Formula (VIII) wherein R⁴ and R⁵ are eachmethyl. In another embodiment, the FXR modulator is a compound ofFormula (VIII) wherein R⁴ and R⁵ form an optionally substitutedC₃-C₆cycloalkyl ring or an optionally substituted C₂-C₇heterocycloalkylring. In some embodiments, the FXR modulator is a compound of Formula(VIII) wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkylring. In some embodiments, the FXR modulator is a compound of Formula(VIII) wherein R⁴ and R⁵ form an optionally substitutedC₂-C₇heterocycloalkyl ring.

In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (VIII)wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (VIII) wherein R⁶and R⁷ are each independently optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula (VIII)wherein R⁶ and R⁷ are each methyl. In another embodiment, the FXRmodulator is a compound of Formula (VIII) wherein R⁶ and R⁷ are eachhydrogen.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R² is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is —C(O)OR²⁵. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIII) wherein R² is —C(O)OR²⁵, and R²⁵ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIII) wherein R² is —C(O)OR²⁵, and R²⁵ is independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is —C(O)OR²⁵, andR²⁵ is hydrogen. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIII) whereinR² is —C(O)OR²⁵, and R²⁵ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIII) wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIII) whereinR² is —C(O)OR²⁵, and R²⁵ is methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIII) wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is —C(O)N(R²⁵)R²⁶.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is —C(O)N(R²⁵)R²⁶,and R²⁵ and R²⁶ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵and R²⁶ are each independently optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIII) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently unsubstituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (VIII) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶are methyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VIII) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIII) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIII) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIII) whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIII) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIII) whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIII) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIII) whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R¹ is selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R¹ is hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIII) wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VIII) wherein R¹ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIII) whereinR¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R¹ and R² togetherwith the carbon atoms to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring or an optionally substitutedheteroaryl ring. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIII) whereinR¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIII) wherein R¹ and R² together with the carbonatoms to which they are attached, form an optionally substitutedheteroaryl ring.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R⁸ is selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedheteroaryl, optionally substituted C₂-C₉heterocycloalkyl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIII) wherein R⁸ is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (VIII) wherein R⁸ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIII) wherein R⁸ is methyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIII) wherein R⁸ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VIII) wherein R⁸ is ethyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIII) wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIII) whereinR⁸ is hydrogen.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIIa), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIIb), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIIc), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIId), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIIe), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIIf), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIIg), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, or 2.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIIh), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIIi), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In a further embodiment of the aforementioned embodiments providedherein, the FXR modulator compound of Formula (VIII) has the structureof Formula (VIIIj), or a pharmaceutically acceptable salt, stereoisomer,or solvate thereof:

wherein:

-   -   each R¹¹ is independently selected from the group consisting of        halogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,        C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl,        C₂-C₉heterocycloalkyl, aryl, heteroaryl, —C(O)OR¹²,        —C(O)N(R¹³)R¹⁴;    -   each R¹² is independently selected from the group consisting of        hydrogen and C₁-C₆alkyl;    -   each R¹³ and R¹⁴ are each independently selected from the group        consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together        with the nitrogen atom to which they are attached, form an        optionally substituted C₂-C₉heterocycloalkyl ring; and    -   n is 0, 1, 2, or 3.

In some embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein n is 0. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein n is 1. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein n is 2. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein n is 1 and R¹¹ is selected from the groupconsisting of halogen, —CN, amino, alkylamino, C₁-C₆alkyl,C₁-C₆haloalkyl, C₁-C₆alkoxy, and C₁-C₆haloalkoxy. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein n is 1 and R¹¹ is selectedfrom the group consisting of halogen, —CN, C₁-C₆alkyl, and C₁-C₆alkoxy.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein n is 1 andR¹¹ is halogen.

In one embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein p is 0. In another embodiment, the FXR modulatoris a compound of Formula (VIIIa)-(VIIIj) wherein p is 1. In anotherembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein p is 2. In another embodiment, the FXR modulator is a compoundof Formula (VIIIa)-(VIIIj) wherein p is 3. In another embodiment, theFXR modulator is a compound of Formula (VIIIa)-(VIIIj) wherein p is 4.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein p is 2 and each R³¹ is independently halogen,—OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (VIIIa)-(VIIIj) wherein p is 2and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein p is 2 and each R³¹ is halogen. Inanother embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein p is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is F, p is 2, and each R³¹ is independentlyhalogen, —OH, —CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl,optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R³⁰ is F, p is 2 and each R³¹ is independently halogen, oroptionally substituted C₁-C₆alkyl. In another embodiment, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R³⁰ is F, pis 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (VIIIa)-(VIIIj) wherein R³⁰ is F, p is 2 andeach R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein p is 1 and R³¹ is halogen, or optionallysubstituted C₁-C₆alkyl. In another embodiment, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein p is 1 and R³¹ is halogen.In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein p is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is F, p is 1 and R³¹ is halogen, —OH, —CN,—NO₂, —NH₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionallysubstituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (VIIIa)-(VIIIj) wherein R³⁰ is F,p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is F, p is 1 and R³¹ is halogen. In anotherembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R³⁰ is F, p is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein r is 0. In another embodiment, the FXR modulatoris a compound of Formula (VIIIa)-(VIIIj) wherein r is 1. In anotherembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein r is 2. In another embodiment, the FXR modulator is a compoundof Formula (VIIIa)-(VIIIj) wherein r is 3. In another embodiment, theFXR modulator is a compound of Formula (VIIIa)-(VIIIj) wherein r is 4.In one embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein each R³² and R³³ are hydrogen. In oneembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R³⁴ and R³⁵ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, and optionally substitutedC₂-C₉heterocycloalkyl. In another embodiment, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen,C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In anotherembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R³⁴ and R³⁵ together with the nitrogen atom to which they areattached form an optionally substituted C₂-C₉heterocycloalkyl ring. Inanother embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁴ and R³⁵ together with the nitrogen atom towhich they are attached form a pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, or methylpiperazinyl. In another embodiment, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R³⁴ and R³⁵together with the nitrogen atom to which they are attached form amorpholinyl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R³⁴ and R³⁵ together with the nitrogenatom to which they are attached form an optionally substitutedheteroaryl ring. In another embodiment, the FXR modulator is a compoundof Formula (VIIIa)-(VIIIj) wherein R³⁴ and R³⁵ together with thenitrogen atom to which they are attached form an imidazolyl, pyrazolyl,or pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (VIIIa)-(VIIIj) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

and p is 0.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

In one embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein t is 2. In another embodiment, the FXR modulatoris a compound of Formula (VIIIa)-(VIIIj) wherein t is 3. In anotherembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein t is 4. In one embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein each R³² and R³³ are hydrogen. In oneembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R³⁴ and R³⁵ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, and optionally substitutedC₂-C₉heterocycloalkyl. In another embodiment, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R³⁴ and R³⁵ are eachindependently selected from the group consisting of hydrogen,C₁-C₆alkyl, C₃-C₈cycloalkyl, and C₂-C₉heterocycloalkyl. In anotherembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R³⁴ and R³⁵ together with the nitrogen atom to which they areattached form an optionally substituted C₂-C₉heterocycloalkyl ring. Inanother embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁴ and R³⁵ together with the nitrogen atom towhich they are attached form a pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, or methylpiperazinyl. In another embodiment, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R³⁴ and R³⁵together with the nitrogen atom to which they are attached form amorpholinyl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R³⁴ and R³⁵ together with the nitrogenatom to which they are attached form an optionally substitutedheteroaryl ring. In another embodiment, the FXR modulator is a compoundof Formula (VIIIa)-(VIIIj) wherein R³⁴ and R³⁵ together with thenitrogen atom to which they are attached form an imidazolyl, pyrazolyl,pyrrolyl.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R³⁰ is

p is 2 and each R³¹ is halogen. In another embodiment, the FXR modulatoris a compound of Formula (VIIIa)-(VIIIj) wherein R³⁰ is

p is 2 and each R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In anotherembodiment, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. Inanother embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

p is 1 and R³¹ is halogen. In another embodiment, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R³⁰ is

p is 1 and R³¹ is F.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R³⁰ is

and p is 0.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R⁴ and R⁵ are each independently selected fromthe group consisting of hydrogen, halogen, and optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R⁴ and R⁵ are each hydrogen.In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R⁴ and R⁵ are each independently optionallysubstituted C₁-C₆alkyl. In another embodiment, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R⁴ and R⁵ are each methyl.In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R⁴ and R⁵ form an optionally substitutedC₃-C₆cycloalkyl ring or an optionally substituted C₂-C₇heterocycloalkylring. In some embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R⁴ and R⁵ form an optionally substitutedC₃-C₆cycloalkyl ring. In some embodiments, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R⁴ and R⁵ form an optionallysubstituted C₂-C₇heterocycloalkyl ring.

In another embodiment, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R⁶ and R⁷ are each independently selected fromthe group consisting of hydrogen, halogen, and optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R⁶ and R⁷ are each independentlyselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In another embodiment, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R⁶ and R⁷ are eachindependently optionally substituted C₁-C₆alkyl. In another embodiment,the FXR modulator is a compound of Formula (VIIIa)-(VIIIj) wherein R⁶and R⁷ are each methyl. In another embodiment, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R⁶ and R⁷ are each hydrogen.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² isselected from the group consisting of —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is—C(O)OR²⁵. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is—C(O)OR²⁵, and R²⁵ is independently selected from the group consistingof hydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R² is —C(O)OR²⁵, and R²⁵ is independentlyselected from the group consisting of hydrogen, and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R² is —C(O)OR²⁵, and R²⁵ is hydrogen. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R² is —C(O)OR²⁵, and R²⁵ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R² is —C(O)OR²⁵, and R²⁵ is unsubstituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIIIa)-(VIIIj) wherein R² is —C(O)OR²⁵, andR²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R² is —C(O)OR²⁵, and R²⁵ is isopropyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is—C(O)N(R²⁵)R²⁶. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected from thegroup consisting of hydrogen, and optionally substituted C₁-C₆alkyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (VIIIa)-(VIIIj) wherein R² is —C(O)N(R²⁵)R²⁶, andR²⁵ and R²⁶ are each independently unsubstituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIIIa)-(VIIIj) wherein R² is —C(O)N(R²⁵)R²⁶,R²⁵ is hydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ aremethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R¹ isselected from the group consisting of hydrogen and optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R¹ is hydrogen. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (VIIIa)-(VIIIj)wherein R¹ is optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R¹ is unsubstituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (VIIIa)-(VIIIj) wherein R¹ is methyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R⁸ isselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted heteroaryl, optionally substitutedC₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R⁸ is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (VIIIa)-(VIIIj) wherein R⁸ is optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R⁸ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (VIIIa)-(VIIIj) wherein R⁸ isoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R⁸ is methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R⁸ is ethyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(VIIIa)-(VIIIj) wherein R⁸ is hydrogen.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(IX), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴ and R⁵ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and    optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵ together with the    carbon atom to which they are attached, form an optionally    substituted C₃-C₆cycloalkyl ring or an optionally substituted    C₂-C₇heterocycloalkyl ring;-   R⁶ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and    —C(O)N(R²⁷)R²⁸;-   R⁷ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally    substituted C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶,

-   R⁹ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R⁸ and R⁹    together with the carbon atoms to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring or an optionally    substituted heteroaryl ring;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²⁷ and R²⁸ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the    nitrogen atom to which they are attached, form an optionally    substituted C₂-C₉heterocycloalkyl ring; or a pharmaceutically    acceptable salt, stereoisomer, or solvate thereof.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is a DPP-IVinhibitor, an SGLT2 inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound of Formula(X), or a pharmaceutically acceptable salt, stereoisomer, or solvatethereof:

wherein:

-   R¹ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionally    substituted aryl, optionally substituted heteroaryl, optionally    substituted C₃-C₈cycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,    —N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,    —C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,    —C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,    —C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵;-   R² is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,    optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, and optionally    substituted —(C₁-C₂alkylene)-(heteroaryl);-   R³ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰, —S(O)₂R²⁰,    —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,    —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,    —N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,    —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and    —P(O)(OR¹⁹)OR²⁰;-   R⁴ and R⁵ are each independently selected from the group consisting    of hydrogen, halogen, optionally substituted C₁-C₆alkyl, optionally    substituted C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and    optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵ together with the    carbon atom to which they are attached, form an optionally    substituted C₃-C₆cycloalkyl ring or an optionally substituted    C₂-C₇heterocycloalkyl ring;-   R⁶ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and    —C(O)N(R²⁷)R²⁸;-   R⁷ is selected from the group consisting of hydrogen, halogen,    optionally substituted C₁-C₆alkyl, optionally substituted    C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally    substituted C₂-C₆alkynyl;-   R⁸ is selected from the group consisting of —CN, —C(O)OR²⁵,    —C(O)N(R²⁵)R²⁶;

-   R⁹ is selected from the group consisting of hydrogen, optionally    substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,    optionally substituted C₂-C₆alkynyl, optionally substituted    C₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R⁸ and R⁹    together with the carbon atoms to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring or an optionally    substituted heteroaryl ring;-   R¹⁰, R¹³ and R¹⁴ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R¹¹ and R¹² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R¹⁵ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl);-   R¹⁹, R²⁰, and R²³ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²¹ and R²² are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₂-C₆alkenyl, optionally substituted    C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally    substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),    optionally substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or optionally R²¹ and R²² together    with the nitrogen atom to which they are attached, form an    optionally substituted C₂-C₉heterocycloalkyl ring;-   R²⁴ is selected from the group consisting of optionally substituted    C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally    substituted C₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl,    optionally substituted aryl optionally substituted    —(C₁-C₂alkylene)-(aryl), optionally substituted    C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and    optionally substituted —(C₁-C₂alkylene)-(heteroaryl); and-   R²⁵ and R²⁶ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl);-   R²⁷ and R²⁸ are each independently selected from the group    consisting of hydrogen, optionally substituted C₁-C₆alkyl,    optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,    optionally substituted —(C₁-C₂alkylene)-(aryl), optionally    substituted C₂-C₉heterocycloalkyl, optionally substituted    heteroaryl, and optionally substituted    —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the    nitrogen atom to which they are attached, form an optionally    substituted C₂-C₉heterocycloalkyl ring; or a pharmaceutically    acceptable salt, stereoisomer, or solvate thereof.

In one embodiment, the FXR modulator is a compound of Formula (IX) or(X) wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (IX)or (X) wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (IX) or (X)wherein R⁴ and R⁵ are each hydrogen. In another embodiment, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁴ and R⁵ areeach independently optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (IX) or (X)wherein R⁴ and R⁵ are each methyl.

In another embodiment, the FXR modulator is a compound of Formula (IX)or (X) wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In another embodiment, the FXR modulator is a compound of Formula (IX)or (X) wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In anotherembodiment, the FXR modulator is a compound of Formula (IX) or (X)wherein R⁶ and R⁷ are each independently optionally substitutedC₁-C₆alkyl. In another embodiment, the FXR modulator is a compound ofFormula (IX) or (X) wherein R⁶ and R⁷ are each methyl. In anotherembodiment, the FXR modulator is a compound of Formula (IX) or (X)wherein R⁶ and R⁷ are each hydrogen.

In another embodiment, the FXR modulator is a compound of Formula (IX)or (X) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independentlyoptionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (IX) or (X) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰is optionally substituted heteroaryl. In another embodiment, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (IX) or (X) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl.

In another embodiment, the FXR modulator is a compound of Formula (IX)or (X) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independentlyoptionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ isoptionally substituted aryl. In another embodiment, the FXR modulator isa compound of Formula (IX) or (X) wherein R⁶ and R⁷ are hydrogen, R⁴ andR⁵ are independently optionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰,and R²⁰ is optionally substituted heteroaryl. In another embodiment, theFXR modulator is a compound of Formula (IX) or (X) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (IX) or (X) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl.

In another embodiment, the FXR modulator is a compound of Formula (IX)or (X) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independentlyoptionally substituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogenand R²² is optionally substituted aryl. In another embodiment, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are independently optionally substituted C₁-C₆alkyl,R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedheteroaryl. In another embodiment, the FXR modulator is a compound ofFormula (IX) or (X) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted aryl. In another embodiment, the FXR modulator is a compoundof Formula (IX) or (X) wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ aremethyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionallysubstituted heteroaryl.

In a further embodiment of the aforementioned embodiments is a compoundof Formula (VIII) wherein R⁸ is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is —C(O)OR²⁵.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is —C(O)OR²⁵,and R²⁵ is independently selected from the group consisting of hydrogen,optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(IX) or (X) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is independently selectedfrom the group consisting of hydrogen, and optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (IX) or (X) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is hydrogen. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(IX) or (X) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (IX) or (X) wherein R⁸ is—C(O)OR²⁵, and R²⁵ is unsubstituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (IX) or (X) wherein R⁸ is —C(O)OR²⁵, and R²⁵ is methyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (IX) or (X) wherein R⁸ is —C(O)OR²⁵, and R²⁵ isethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is—C(O)N(R²⁵)R²⁶. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IX) or (X)wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are each independently selected from thegroup consisting of hydrogen, and optionally substituted C₁-C₆alkyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (IX) or (X) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ areeach independently optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (IX) or (X) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (IX) or (X) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵and R²⁶ are each independently unsubstituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (IX) or (X) wherein R⁸ is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(IX) or (X) wherein R⁸ is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (IX) or (X) wherein R⁸ is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IX) or (X)wherein R⁸ is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (IX) or (X) wherein R⁸ is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IX) or (X)wherein R⁸ is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R⁸ is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (IX) or (X) wherein R⁸ is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IX) or (X)wherein R⁸ is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R² is selectedfrom the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted heteroaryl, optionally substitutedC₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(IX) or (X) wherein R² is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (IX) or (X) wherein R² is optionally substituted C₁-C₆alkyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R² is methyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R² is ethyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (IX) or (X) wherein R² is hydrogen.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R¹ is selectedfrom the group consisting of hydrogen, halogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted —(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted—(C₁-C₂alkylene)-(heteroaryl), and —OR¹⁰. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(IX) or (X) wherein R¹ is hydrogen. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(IX) or (X) wherein R¹ is halogen. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(IX) or (X) wherein R¹ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (IX) or (X) wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (IX) or (X)wherein R¹ is optionally substituted C₂-C₆alkynyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (IX) or (X) wherein R¹ is —OR¹⁰ and R¹⁰ is hydrogen.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (IX) or (X) wherein R¹ is —OR¹⁰ andR¹⁰ is optionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(IX) or (X) wherein R¹ is —OR¹⁰ and R¹⁰ is methyl.

In some embodiments, the FXR modulator is a compound of Formula (XI):

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

-   -    or R¹ and R² together with the carbon atoms to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring or an optionally substituted heteroaryl ring;    -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ are each independently selected from the group        consisting of hydrogen, halogen, —CN, amino, alkylamino,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₃-C₈cycloalkyl, optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted aryl,        and optionally substituted heteroaryl;    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R²¹ and        R²² together with the nitrogen atom to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring.

In some embodiments the FXR modulator is a compound of Formula (XI),wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XI),wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XI), wherein R⁴and R⁵ are each hydrogen. In some embodiments the FXR modulator is acompound of Formula (XI), wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In some embodiments the FXR modulatoris a compound of Formula (XI), wherein R⁴ and R⁵ are each methyl. Insome embodiments the FXR modulator is a compound of Formula (XI),wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkyl ring oran optionally substituted C₂-C₇heterocycloalkyl ring. In someembodiments is a compound of Formula (XI) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring. In some embodiments is acompound of Formula (XI) wherein R⁴ and R⁵ form an optionallysubstituted C₂-C₇heterocycloalkyl ring.

In some embodiments the FXR modulator is a compound of Formula (XI),wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XI),wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XI), wherein R⁶and R⁷ are each independently optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XI), wherein R⁶and R⁷ are each methyl. In some embodiments the FXR modulator is acompound of Formula (XI), wherein R⁶ and R⁷ are each hydrogen.

In some embodiments the FXR modulator is a compound of Formula (XI),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XI), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰is optionally substituted heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XI), wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionally substitutedaryl. In some embodiments the FXR modulator is a compound of Formula(XI), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is—C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XI),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XI), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, andR²⁰ is optionally substituted heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XI), wherein R⁶ and R⁷ are hydrogen,R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionally substitutedaryl. In some embodiments the FXR modulator is a compound of Formula(XI), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is—S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XI),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted aryl. In some embodiments the FXR modulator is acompound of Formula (XI), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²²,R²¹ is hydrogen and R²² is optionally substituted heteroaryl. In someembodiments the FXR modulator is a compound of Formula (XI), wherein R⁶and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted aryl. In some embodiments theFXR modulator is a compound of Formula (XI), wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogenand R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is selected from thegroup consisting of —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is —C(O)OR²⁵. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XI), wherein R² is —C(O)OR²⁵, and R²⁵ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XI), wherein R² is —C(O)OR²⁵, and R²⁵ is independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is —C(O)OR²⁵, andR²⁵ is hydrogen. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XI), wherein R²is —C(O)OR²⁵, and R²⁵ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XI), wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XI), wherein R²is —C(O)OR²⁵, and R²⁵ is methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XI), wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is —C(O)N(R²⁵)R²⁶.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is —C(O)N(R²⁵)R²⁶,and R²⁵ and R²⁶ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XI), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XI), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XI), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ andR²⁶ are each independently optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XI), wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XI), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently unsubstituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (XI), wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶ aremethyl. In a further embodiment of the aforementioned embodiments, theFXR modulator is a compound of Formula (XI), wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XI), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XI), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XI), wherein R²is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XI), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XI), wherein R²is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XI), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XI), wherein R²is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R¹ is selected from thegroup consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R¹ is hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XI), wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XI), wherein R¹ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XI), wherein R¹is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R¹ and R² together withthe carbon atoms to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring or an optionally substitutedheteroaryl ring. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XI), wherein R¹and R² together with the carbon atoms to which they are attached, forman optionally substituted C₂-C₉heterocycloalkyl ring. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XI), wherein R¹ and R² together with the carbonatoms to which they are attached, form an optionally substitutedheteroaryl ring.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R⁸ is selected from thegroup consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedheteroaryl, optionally substituted C₂-C₉heterocycloalkyl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XI), wherein R⁸ is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (XI), wherein R⁸ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XI), wherein R⁸ is methyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XI), wherein R⁸ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XI), wherein R⁸ is ethyl. Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XI), wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XI), wherein R⁸is hydrogen.

In some embodiments of a compound of Formula (XI), the FXR modulator isa compound of Formula (XIa), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

wherein:

-   -   R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIa), wherein R⁴and R⁵ are each hydrogen. In some embodiments the FXR modulator is acompound of Formula (XIa), wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In some embodiments the FXR modulatoris a compound of Formula (XIa), wherein R⁴ and R⁵ are each methyl. Insome embodiments the FXR modulator is a compound of Formula (XIa),wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkyl ring oran optionally substituted C₂-C₇heterocycloalkyl ring. In someembodiments is a compound of Formula (XIa) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring. In some embodiments is acompound of Formula (XIa) wherein R⁴ and R⁵ form an optionallysubstituted C₂-C₇heterocycloalkyl ring.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIa), wherein R⁶and R⁷ are each independently optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIa), wherein R⁶and R⁷ are each methyl. In some embodiments the FXR modulator is acompound of Formula (XIa), wherein R⁶ and R⁷ are each hydrogen.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰is optionally substituted heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XIa), wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, andR²⁰ is optionally substituted heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XIa), wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted aryl. In some embodiments the FXR modulator is acompound of Formula (XIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²²,R²¹ is hydrogen and R²² is optionally substituted heteroaryl. In someembodiments the FXR modulator is a compound of Formula (XIa), wherein R⁶and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted aryl. In some embodiments theFXR modulator is a compound of Formula (XIa), wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogenand R²² is optionally substituted heteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein p is 0. In some embodiments the FXR modulator is a compound ofFormula (XIa), wherein p is 1. In some embodiments the FXR modulator isa compound of Formula (XIa), wherein p is 2. In some embodiments the FXRmodulator is a compound of Formula (XIa), wherein p is 3. In someembodiments the FXR modulator is a compound of Formula (XIa), wherein pis 4.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein p is 2 and each R³¹ is independently halogen, —OH, —CN, —NO₂,—NH₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionallysubstituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XIa), wherein p is 2 and each R³¹ isindependently halogen, or optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIa), wherein pis 2 and each R³¹ is halogen. In some embodiments the FXR modulator is acompound of Formula (XIa), wherein p is 2 and each R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is F, p is 2, and each R³¹ is independently halogen, —OH,—CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XIa), wherein R³⁰ is F, p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In some embodimentsthe FXR modulator is a compound of Formula (XIa), wherein R³⁰ is F, p is2 and each R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Insome embodiments the FXR modulator is a compound of Formula (XIa),wherein p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XIa),wherein p is 1 and R³¹ is halogen. In some embodiments the FXR modulatoris a compound of Formula (XIa), wherein p is 1 and R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is F, p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In some embodiments the FXR modulator is a compound ofFormula (XIa), wherein R³⁰ is F, p is 1 and R³¹ is halogen, oroptionally substituted C₁-C₆alkyl. In some embodiments the FXR modulatoris a compound of Formula (XIa), wherein R³⁰ is F, p is 1 and R³¹ ishalogen. In some embodiments the FXR modulator is a compound of Formula(XIa), wherein R³⁰ is F, p is 1 and R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In some embodiments the FXR modulator is a compound ofFormula (XIa), wherein R³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In

some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is p is 2 and each R³¹ is halogen. In some embodiments theFXR modulator is a compound of Formula (XIa), wherein R³⁰ is

p is 2 and each R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In someembodiments the FXR modulator is a compound of Formula (XIa), whereinR³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIa), whereinR³⁰ is

p is 1 and R³¹ is halogen. In some embodiments the FXR modulator is acompound of Formula (XIa), wherein R³⁰ is

p is 1 and R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is

and p is O.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In some embodiments the FXR modulator is a compound ofFormula (XIa), wherein R³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In some embodiments the FXR modulator is a compound ofFormula (XIa), wherein R³⁰ is

p is 2 and each R³¹ is halogen. In some embodiments the FXR modulator isa compound of Formula (XIa), wherein R³⁰ is

p is 2 and each R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In someembodiments the FXR modulator is a compound of Formula (XIa), whereinR³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIa), whereinR³⁰ is

p is 1 and R³¹ is halogen. In some embodiments the FXR modulator is acompound of Formula (XIa), wherein R³⁰ is

p is 1 and R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIa),wherein R³⁰ is

and p is 0.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is selected fromthe group consisting of —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is —C(O)OR²⁵. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIa), wherein R² is —C(O)OR²⁵, and R²⁵ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XIa), wherein R² is —C(O)OR²⁵, and R²⁵ is independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is —C(O)OR²⁵, andR²⁵ is hydrogen. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIa), whereinR² is —C(O)OR²⁵, and R²⁵ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIa), wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIa), whereinR² is —C(O)OR²⁵, and R²⁵ is methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XIa), wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is —C(O)N(R²⁵)R²⁶.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is —C(O)N(R²⁵)R²⁶,and R²⁵ and R²⁶ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵and R²⁶ are each independently optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIa), wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently unsubstituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (XIa), wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶are methyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XIa), wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIa), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIa), whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIa), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIa), whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIa), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIa), whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R¹ is selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R¹ is hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIa), wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XIa), wherein R¹ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIa), whereinR¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R¹ and R² togetherwith the carbon atoms to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring or an optionally substitutedheteroaryl ring. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIa), whereinR¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XIa), wherein R¹ and R² together with the carbonatoms to which they are attached, form an optionally substitutedheteroaryl ring.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R⁸ is selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedheteroaryl, optionally substituted C₂-C₉heterocycloalkyl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIa), wherein R⁸ is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (XIa), wherein R⁸ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIa), wherein R⁸ is methyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XIa), wherein R⁸ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XIa), wherein R⁸ is ethyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIa), wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIa), whereinR⁸ is hydrogen.

In some embodiments, the FXR modulator is a compound of Formula (XII):

wherein:

-   -   R¹ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R² is selected from the group consisting of —CN, —C(O)OR²⁵,        —C(O)N(R²⁵)R²⁶,

-   -    or R¹ and R² together with the carbon atoms to which they are        attached, form an optionally substituted C₂-C₉heterocycloalkyl        ring or an optionally substituted heteroaryl ring;    -   R³ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈cycloalkyl, optionally substituted aryl, optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        heteroaryl, optionally substituted C₂-C₉heterocycloalkyl,        optionally substituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰,        —C(O)OR²⁰, —S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴,        —C(O)N(R²³)N(R²¹)R²², —C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰,        —N(R²³)C(O)N(R²¹)R²², —N(R²³)C(O)N(R²¹)S(O)₂R²⁴,        —N(R²⁰)C(O)N(R²³)N(R²¹)R²², —N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴,        —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and —P(O)(OR¹⁹)OR²⁰;    -   R⁴ and R⁵ are each independently selected from the group        consisting of hydrogen, halogen, optionally substituted        C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally        substituted C₂-C₆alkenyl, and optionally substituted        C₂-C₆alkynyl; or R⁴ and R⁵ together with the carbon atom to        which they are attached, form an optionally substituted        C₃-C₆cycloalkyl ring or an optionally substituted        C₂-C₇heterocycloalkyl ring;    -   R⁶ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and        —C(O)N(R²⁷)R²⁸;    -   R⁷ is selected from the group consisting of hydrogen, halogen,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionally        substituted C₂-C₆alkynyl;    -   R⁸ is selected from the group consisting of hydrogen, optionally        substituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,        optionally substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl,        optionally substituted C₂-C₉heterocycloalkyl, and optionally        substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R⁹ and R¹⁰ are each independently selected from the group        consisting of hydrogen, halogen, —CN, amino, alkylamino,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₃-C₈cycloalkyl, optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted aryl,        and optionally substituted heteroaryl;    -   R¹⁹, R²⁰, and R²³ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²¹ and R²² are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₂-C₆alkenyl, optionally substituted        C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionally        substituted aryl, optionally substituted        —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl); or R²¹ and        R²² together with the nitrogen atom to which they are attached,        form an optionally substituted C₂-C₉heterocycloalkyl ring;    -   R²⁴ is selected from the group consisting of optionally        substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,        optionally substituted C₂-C₆alkynyl, optionally substituted        C₃-C₈ cycloalkyl, optionally substituted aryl optionally        substituted —(C₁-C₂alkylene)-(aryl), optionally substituted        C₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and        optionally substituted —(C₁-C₂alkylene)-(heteroaryl);    -   R²⁵ and R²⁶ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); and    -   R²⁷ and R²⁸ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, optionally substituted        aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally        substituted C₂-C₉heterocycloalkyl, optionally substituted        heteroaryl, and optionally substituted        —(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the        nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring.

In some embodiments the FXR modulator is a compound of Formula (XII),wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XII),wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XII), wherein R⁴and R⁵ are each hydrogen. In some embodiments the FXR modulator is acompound of Formula (XII), wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In some embodiments the FXR modulatoris a compound of Formula (XII), wherein R⁴ and R⁵ are each methyl. Insome embodiments the FXR modulator is a compound of Formula (XII),wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkyl ring oran optionally substituted C₂-C₇heterocycloalkyl ring. In someembodiments is a compound of Formula (XII) wherein R⁴ andR^(5 form an optionally substituted C) ₃-C₆cycloalkyl ring. In someembodiments is a compound of Formula (XII) wherein R⁴ and R⁵ form anoptionally substituted C₂-C₇heterocycloalkyl ring.

In some embodiments the FXR modulator is a compound of Formula (XII),wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XII),wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XII), wherein R⁶and R⁷ are each independently optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XII), wherein R⁶and R⁷ are each methyl. In some embodiments the FXR modulator is acompound of Formula (XII), wherein R⁶ and R⁷ are each hydrogen.

In some embodiments the FXR modulator is a compound of Formula (XII),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XII), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰is optionally substituted heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XII), wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XII), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XII),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XII), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, andR²⁰ is optionally substituted heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XII), wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XII), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XII),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted aryl. In some embodiments the FXR modulator is acompound of Formula (XII), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²²,R²¹ is hydrogen and R²² is optionally substituted heteroaryl. In someembodiments the FXR modulator is a compound of Formula (XII), wherein R⁶and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ ishydrogen and R²² is optionally substituted aryl. In some embodiments theFXR modulator is a compound of Formula (XII), wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogenand R²² is optionally substituted heteroaryl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is selected fromthe group consisting of —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is —C(O)OR²⁵. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XII), wherein R² is —C(O)OR²⁵, and R²⁵ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XII), wherein R² is —C(O)OR²⁵, and R²⁵ is independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is —C(O)OR²⁵, andR²⁵ is hydrogen. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XII), whereinR² is —C(O)OR²⁵, and R²⁵ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XII), wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XII), whereinR² is —C(O)OR²⁵, and R²⁵ is methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XII), wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is —C(O)N(R²⁵)R²⁶.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is —C(O)N(R²⁵)R²⁶,and R²⁵ and R²⁶ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XII), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XII), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XII), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵and R²⁶ are each independently optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XII), wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XII), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶are each independently unsubstituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (XII), wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ is hydrogen, and R²⁶are methyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XII), wherein R² is—C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XII), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XII), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XII), whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XII), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XII), whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XII), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XII), whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R¹ is selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R¹ is hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XII), wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XII), wherein R¹ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XII), whereinR¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R¹ and R² togetherwith the carbon atoms to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring or an optionally substitutedheteroaryl ring. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XII), whereinR¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XII), wherein R¹ and R² together with the carbonatoms to which they are attached, form an optionally substitutedheteroaryl ring.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R⁸ is selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedheteroaryl, optionally substituted C₂-C₉heterocycloalkyl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XII), wherein R⁸ is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (XII), wherein R⁸ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XII), wherein R⁸ is methyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XII), wherein R⁸ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XII), wherein R⁸ is ethyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XII), wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XII), whereinR⁸ is hydrogen.

In some embodiments of a compound of Formula (XII), the FXR modulator isa compound of Formula (XIIa), or a pharmaceutically acceptable salt,stereoisomer, or solvate thereof:

wherein:

-   -   R³⁰ is halogen,

-   -   each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,        optionally substituted C₁-C₆alkyl, optionally substituted        C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionally        substituted C₃-C₈cycloalkyl, optionally substituted        C₂-C₉heterocycloalkyl, aryl, or heteroaryl;    -   each R³² and R³³ are each independently selected from the group        consisting of hydrogen, halogen, and C₁-C₆alkyl;    -   R³⁴ and R³⁵ are each independently selected from the group        consisting of hydrogen, optionally substituted C₁-C₆alkyl,        optionally substituted C₃-C₈cycloalkyl, and optionally        substituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with        the nitrogen atom to which they are attached, form an optionally        substituted C₂-C₉heterocycloalkyl ring;    -   p is 0, 1, 2, 3, or 4;    -   r is 0, 1, 2, 3, or 4; and    -   t is 2, 3, or 4.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R⁴ and R⁵ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIIa), whereinR⁴ and R⁵ are each hydrogen. In some embodiments the FXR modulator is acompound of Formula (XIIa), wherein R⁴ and R⁵ are each independentlyoptionally substituted C₁-C₆alkyl. In some embodiments the FXR modulatoris a compound of Formula (XIIa), wherein R⁴ and R⁵ are each methyl. Insome embodiments the FXR modulator is a compound of Formula (XIIa),wherein R⁴ and R⁵ form an optionally substituted C₃-C₆cycloalkyl ring oran optionally substituted C₂-C₇heterocycloalkyl ring. In someembodiments is a compound of Formula (XIIa) wherein R⁴ and R⁵ form anoptionally substituted C₃-C₆cycloalkyl ring. In some embodiments is acompound of Formula (XIIa) wherein R⁴ and R⁵ form an optionallysubstituted C₂-C₇heterocycloalkyl ring.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen, halogen, and optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R⁶ and R⁷ are each independently selected from the groupconsisting of hydrogen and optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIIa), whereinR⁶ and R⁷ are each independently optionally substituted C₁-C₆alkyl. Insome embodiments the FXR modulator is a compound of Formula (XIIa),wherein R⁶ and R⁷ are each methyl. In some embodiments the FXR modulatoris a compound of Formula (XIIa), wherein R⁶ and R⁷ are each hydrogen.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —C(O)R²⁰, and R²⁰is optionally substituted heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XIIa), wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —C(O)R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)R²⁰, and R²⁰ is optionally substituted heteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ areindependently optionally substituted C₁-C₆alkyl, R³ is —S(O)₂R²⁰, andR²⁰ is optionally substituted heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XIIa), wherein R⁶ and R⁷ arehydrogen, R⁴ and R⁵ are methyl, R³ is —S(O)₂R²⁰, and R²⁰ is optionallysubstituted aryl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —S(O)₂R²⁰, and R²⁰ is optionally substituted heteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are independently optionallysubstituted C₁-C₆alkyl, R³ is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² isoptionally substituted aryl. In some embodiments the FXR modulator is acompound of Formula (XIIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵are independently optionally substituted C₁-C₆alkyl, R³ is—C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedheteroaryl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³is —C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedaryl. In some embodiments the FXR modulator is a compound of Formula(XIIa), wherein R⁶ and R⁷ are hydrogen, R⁴ and R⁵ are methyl, R³ is—C(O)N(R²¹)R²², R²¹ is hydrogen and R²² is optionally substitutedheteroaryl.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein p is 0. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein p is 1. In some embodiments the FXR modulator isa compound of Formula (XIIa), wherein p is 2. In some embodiments theFXR modulator is a compound of Formula (XIIa), wherein p is 3. In someembodiments the FXR modulator is a compound of Formula (XIIa), wherein pis 4.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein p is 2 and each R³¹ is independently halogen, —OH, —CN, —NO₂,—NH₂, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine, optionallysubstituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XIIa), wherein p is 2 and each R³¹is independently halogen, or optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIIa), wherein pis 2 and each R³¹ is halogen. In some embodiments the FXR modulator is acompound of Formula (XIIa), wherein p is 2 and each R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R³⁰ is F, p is 2, and each R³¹ is independently halogen, —OH,—CN, —NO₂, —NH₂, optionally substituted C₁-C₆alkyl, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkylamine,optionally substituted C₃-C₈cycloalkyl, optionally substitutedC₂-C₉heterocycloalkyl, aryl, or heteroaryl. In some embodiments the FXRmodulator is a compound of Formula (XIIa), wherein R³⁰ is F, p is 2 andeach R³¹ is independently halogen, or optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R³⁰ is F, p is 2 and each R³¹ is halogen. In some embodimentsthe FXR modulator is a compound of Formula (XIIa), wherein R³⁰ is F, pis 2 and each R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. Insome embodiments the FXR modulator is a compound of Formula (XIIa),wherein p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl.In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein p is 1 and R³¹ is halogen. In some embodiments the FXR modulatoris a compound of Formula (XIIa), wherein p is 1 and R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R³⁰ is F, p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R³⁰ is F, p is 1 and R³¹ is halogen, oroptionally substituted C₁-C₆alkyl. In some embodiments the FXR modulatoris a compound of Formula (XIIa), wherein R³⁰ is F, p is 1 and R³¹ ishalogen. In some embodiments the FXR modulator is a compound of Formula(XIIa), wherein R³⁰ is F, p is 1 and R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R³⁰ is

p is 2 and each R³¹ is halogen. In some embodiments the FXR modulator isa compound of Formula (XIIa), wherein R³⁰ is

p is 2 and each R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In someembodiments the FXR modulator is a compound of Formula (XIIa), whereinR³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIIa), whereinR³⁰ is

p is 1 and R³¹ is halogen. In some embodiments the FXR modulator is acompound of Formula (XIIa), wherein R³⁰ is

p is 1 and R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R³⁰ is

and p is O.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R³⁰ is

p is 2, and each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂,optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy,optionally substituted C₁-C₆alkylamine, optionally substitutedC₃-C₈cycloalkyl, optionally substituted C₂-C₉heterocycloalkyl, aryl, orheteroaryl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R³⁰ is

p is 2 and each R³¹ is independently halogen, or optionally substitutedC₁-C₆alkyl. In some embodiments the FXR modulator is a compound ofFormula (XIIa), wherein R³⁰ is

p is 2 and each R³¹ is halogen. In some embodiments the FXR modulator isa compound of Formula (XIIa), wherein R³⁰ is

p is 2 and each R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R³⁰ is

p is 1 and R³¹ is halogen, —OH, —CN, —NO₂, —NH₂, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl. In someembodiments the FXR modulator is a compound of Formula (XIIa), whereinR³⁰ is

p is 1 and R³¹ is halogen, or optionally substituted C₁-C₆alkyl. In someembodiments the FXR modulator is a compound of Formula (XIIa), whereinR³⁰ is

p is 1 and R³¹ is halogen. In some embodiments the FXR modulator is acompound of Formula (XIIa), wherein R³⁰ is

p is 1 and R³¹ is F.

In some embodiments the FXR modulator is a compound of Formula (XIIa),wherein R³⁰ is

and p is 0.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is selected fromthe group consisting of —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is —CN.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is —C(O)OR²⁵. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIIa), wherein R² is —C(O)OR²⁵, and R²⁵ isindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl). In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XIIa), wherein R² is —C(O)OR²⁵, and R²⁵ is independently selected fromthe group consisting of hydrogen, and optionally substituted C₁-C₆alkyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is —C(O)OR²⁵, andR²⁵ is hydrogen. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIIa), whereinR² is —C(O)OR²⁵, and R²⁵ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIIa), wherein R² is —C(O)OR²⁵, and R²⁵ isunsubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIIa), whereinR² is —C(O)OR²⁵, and R²⁵ is methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XIIa), wherein R² is —C(O)OR²⁵, and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is —C(O)N(R²⁵)R²⁶.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is —C(O)N(R²⁵)R²⁶,and R²⁵ and R²⁶ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, andoptionally substituted C₁-C₆alkyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XIIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵and R²⁶ are each independently optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIIa), wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ is optionally substituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XIIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ andR²⁶ are each independently unsubstituted C₁-C₆alkyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XIIa), wherein R² is —C(O)N(R²⁵)R²⁶, R²⁵ ishydrogen, and R²⁶ are methyl. In a further embodiment of theaforementioned embodiments, the FXR modulator is a compound of Formula(XIIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵ and R²⁶ are methyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIIa), wherein R² is —C(O)N(R²⁵)R²⁶, and R²⁵and R²⁶ are ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIIa), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIIa), whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIIa), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIIa), whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R² is

and R²⁵ is optionally substituted C₁-C₆alkyl. In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIIa), wherein R² is

and R²⁵ is methyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIIa), whereinR² is

and R²⁵ is ethyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R¹ is selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl). Ina further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R¹ is hydrogen. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIIa), wherein R¹ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XIIa), wherein R¹ is methyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R¹ is optionallysubstituted C₂-C₆alkenyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIIa), whereinR¹ is optionally substituted C₂-C₆alkynyl.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R¹ and R² togetherwith the carbon atoms to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring or an optionally substitutedheteroaryl ring. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIIa), whereinR¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XIIa), wherein R¹ and R² together with the carbonatoms to which they are attached, form an optionally substitutedheteroaryl ring.

In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R⁸ is selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedheteroaryl, optionally substituted C₂-C₉heterocycloalkyl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl). In a further embodiment ofthe aforementioned embodiments, the FXR modulator is a compound ofFormula (XIIa), wherein R⁸ is selected from the group consisting ofhydrogen, and optionally substituted C₁-C₆alkyl. In a further embodimentof the aforementioned embodiments, the FXR modulator is a compound ofFormula (XIIa), wherein R⁸ is optionally substituted C₁-C₆alkyl. In afurther embodiment of the aforementioned embodiments, the FXR modulatoris a compound of Formula (XIIa), wherein R⁸ is methyl. In a furtherembodiment of the aforementioned embodiments, the FXR modulator is acompound of Formula (XIIa), wherein R⁸ is optionally substitutedC₁-C₆alkyl. In a further embodiment of the aforementioned embodiments,the FXR modulator is a compound of Formula (XIIa), wherein R⁸ is ethyl.In a further embodiment of the aforementioned embodiments, the FXRmodulator is a compound of Formula (XIIa), wherein R⁸ is optionallysubstituted C₁-C₆alkyl. In a further embodiment of the aforementionedembodiments, the FXR modulator is a compound of Formula (XIIa), whereinR⁸ is hydrogen.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof can be chosen by one skilled in the field toprovide stable moieties and compounds.

In some embodiments of the methods described herein, the FXR modulatoris(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof.

In some embodiments is the administration of an FXR modulator describedherein to a mammal in the treatment of diseases, disorders or conditionsthat would benefit from FXR modulation, wherein the FXR modulator is(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is nonalcoholic steatohepatitis (NASH),hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease,atherosclerotic disease events, atherosclerotic cardiovascular disease,Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity,hyperglycemia, cholestasis, or obesity. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is nonalcoholic steatohepatitis (NASH). In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hyperlipidemia. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hypercholesterolemia. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hypertriglyceridemia. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is dyslipidemia. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is lipodystrophy. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerosis. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerotic disease. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerotic disease events. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerotic cardiovascular disease. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is Syndrome X. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is diabetes mellitus. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is type II diabetes. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is insulin insensitivity. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hyperglycemia. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is cholestasis. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is obesity.

Further disclosed herein, is a method of treating a choleastaticdisorder in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a choleastatic disorder in a subjectin need thereof, comprising administering to the subject in need thereofan effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein thecholestatic disorder is primary biliary cirrhosis. In some embodimentsis a method of treating a cholestatic disorder in a subject in needthereof, comprising administering to the subject in need thereof aneffective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein thecholestatic disorder is primary sclerosing cholangitis. In someembodiments is a method of treating a cholestatic disorder in a subjectin need thereof, comprising administering to the subject in need thereofan effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein thecholestatic disorder is biliary atresia.

Further disclosed herein, is a method of treating fibrosis associatedwith nonalcoholic steatohepatitis (NASH), chronic viral hepatitis, orautoimmune hepatitis, in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating fibrosis associated withnonalcoholic steatohepatitis (NASH), in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating fibrosis associated with chronicviral hepatitis, in a subject in need thereof, comprising administeringto the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating fibrosis associated with autoimmunehepatitis, in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof.

Further disclosed herein, is a method of treating cholesterol gallstonedisease, in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof.

Further disclosed herein, is a method of treating portal hypertension,in a subject in need thereof, comprising administering to the subject inneed thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof.

Further disclosed herein, is a method of treating a gastrointestinaldisorder in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein thegastrointestinal disorder is inflammatory bowel disease. In someembodiments is a method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein thegastrointestinal disorder is irritable bowel syndrome. In someembodiments is a method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein thegastrointestinal disorder is bile acid diarrhea.

Further disclosed herein, is a method of treating a kidney disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a kidney disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein thekidney disorder is diabetic nephropathy. In some embodiments is a methodof treating a kidney disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein thekidney disorder is renal fibrosis. In some embodiments is a method oftreating a kidney disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-6-(3,4-difluorobenzoyl)-N-isopropyl-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxamide(Compound 1), or a pharmaceutically acceptable salt thereof, wherein thekidney disorder is focal segmental glomerulosclerosis.

In some embodiments of the methods described herein, the FXR modulatoris (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof.

In some embodiments is the administration of an FXR modulator describedherein to a mammal in the treatment of diseases, disorders or conditionsthat would benefit from FXR modulation, wherein the FXR modulator is(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is nonalcoholic steatohepatitis (NASH),hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease,atherosclerotic disease events, atherosclerotic cardiovascular disease,Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity,hyperglycemia, cholestasis, or obesity. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is nonalcoholic steatohepatitis (NASH). In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hyperlipidemia. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hypercholesterolemia. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hypertriglyceridemia. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is dyslipidemia. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is lipodystrophy. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerosis. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerotic disease. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerotic disease events. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerotic cardiovascular disease. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is Syndrome X. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is diabetes mellitus. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is type II diabetes. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is insulin insensitivity. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hyperglycemia. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is cholestasis. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is obesity.

Further disclosed herein, is a method of treating a choleastaticdisorder in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a choleastatic disorder in a subjectin need thereof, comprising administering to the subject in need thereofan effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein thecholestatic disorder is primary biliary cirrhosis. In some embodimentsis a method of treating a cholestatic disorder in a subject in needthereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein thecholestatic disorder is primary sclerosing cholangitis. In someembodiments is a method of treating a cholestatic disorder in a subjectin need thereof, comprising administering to the subject in need thereofan effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein thecholestatic disorder is biliary atresia.

Further disclosed herein, is a method of treating fibrosis associatedwith nonalcoholic steatohepatitis (NASH), chronic viral hepatitis, orautoimmune hepatitis, in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating fibrosis associated withnonalcoholic steatohepatitis (NASH), in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating fibrosis associated with chronicviral hepatitis, in a subject in need thereof, comprising administeringto the subject in need thereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating fibrosis associated with autoimmunehepatitis, in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof.

Further disclosed herein, is a method of treating cholesterol gallstonedisease, in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof.

Further disclosed herein, is a method of treating portal hypertension,in a subject in need thereof, comprising administering to the subject inneed thereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof.

Further disclosed herein, is a method of treating a gastrointestinaldisorder in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein thegastrointestinal disorder is inflammatory bowel disease. In someembodiments is a method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein thegastrointestinal disorder is irritable bowel syndrome. In someembodiments is a method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein thegastrointestinal disorder is bile acid diarrhea.

Further disclosed herein, is a method of treating a kidney disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a kidney disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein thekidney disorder is diabetic nephropathy. In some embodiments is a methodof treating a kidney disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein thekidney disorder is renal fibrosis. In some embodiments is a method oftreating a kidney disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl4,4-dimethyl-6-(4-(2-morpholinoethoxy)benzoyl)-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 2), or a pharmaceutically acceptable salt thereof, wherein thekidney disorder is focal segmental glomerulosclerosis.

In some embodiments of the methods described herein, the FXR modulatoris (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof.

In some embodiments is the administration of an FXR modulator describedherein to a mammal in the treatment of diseases, disorders or conditionsthat would benefit from FXR modulation, wherein the FXR modulator is(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is nonalcoholic steatohepatitis (NASH),hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease,atherosclerotic disease events, atherosclerotic cardiovascular disease,Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity,hyperglycemia, cholestasis, or obesity. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is nonalcoholic steatohepatitis (NASH). In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hyperlipidemia. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hypercholesterolemia. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hypertriglyceridemia. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is dyslipidemia. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is lipodystrophy. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerosis. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerotic disease. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerotic disease events. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is atherosclerotic cardiovascular disease. In someembodiments is a method of treating a metabolic disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is Syndrome X. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is diabetes mellitus. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is type II diabetes. In some embodiments is a methodof treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is insulin insensitivity. In some embodiments is amethod of treating a metabolic disorder in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is hyperglycemia. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is cholestasis. In some embodiments is a method oftreating a metabolic disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein themetabolic disorder is obesity.

Further disclosed herein, is a method of treating a choleastaticdisorder in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a choleastatic disorder in a subjectin need thereof, comprising administering to the subject in need thereofan effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein thecholestatic disorder is primary biliary cirrhosis. In some embodimentsis a method of treating a cholestatic disorder in a subject in needthereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein thecholestatic disorder is primary sclerosing cholangitis. In someembodiments is a method of treating a cholestatic disorder in a subjectin need thereof, comprising administering to the subject in need thereofan effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein thecholestatic disorder is biliary atresia.

Further disclosed herein, is a method of treating fibrosis associatedwith nonalcoholic steatohepatitis (NASH), chronic viral hepatitis, orautoimmune hepatitis, in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating fibrosis associated withnonalcoholic steatohepatitis (NASH), in a subject in need thereof,comprising administering to the subject in need thereof an effectivedose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating fibrosis associated with chronicviral hepatitis, in a subject in need thereof, comprising administeringto the subject in need thereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating fibrosis associated with autoimmunehepatitis, in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof.

Further disclosed herein, is a method of treating cholesterol gallstonedisease, in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof.

Further disclosed herein, is a method of treating portal hypertension,in a subject in need thereof, comprising administering to the subject inneed thereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof.

Further disclosed herein, is a method of treating a gastrointestinaldisorder in a subject in need thereof, comprising administering to thesubject in need thereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein thegastrointestinal disorder is inflammatory bowel disease. In someembodiments is a method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein thegastrointestinal disorder is irritable bowel syndrome. In someembodiments is a method of treating a gastrointestinal disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein thegastrointestinal disorder is bile acid diarrhea.

Further disclosed herein, is a method of treating a kidney disorder in asubject in need thereof, comprising administering to the subject in needthereof an effective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof. In someembodiments is a method of treating a kidney disorder in a subject inneed thereof, comprising administering to the subject in need thereof aneffective dose of (E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein thekidney disorder is diabetic nephropathy. In some embodiments is a methodof treating a kidney disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein thekidney disorder is renal fibrosis. In some embodiments is a method oftreating a kidney disorder in a subject in need thereof, comprisingadministering to the subject in need thereof an effective dose of(E)-isopropyl6-(3-fluoro-4-(2-morpholinoethoxy)benzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(Compound 3), or a pharmaceutically acceptable salt thereof, wherein thekidney disorder is focal segmental glomerulosclerosis.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is anCC2/CCR5 antagonist, ASK1 inhibitor, DPP-IV inhibitor, caspase preoteaseinhibitor, an SGLT2 inhibitor, acetyl-CoA carboxylase inhibitor,sodium-bile acide cotransporter-inhibitor, TLR-4 antagonist, PPARalpha/delta agonist, a GLP-1 agonist, or a combination thereof; whereinthe FXR modulator is a compound having the structure:

or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

In some embodiments is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) at least one second agent that is anCC2/CCR5 antagonist, ASK1 inhibitor, DPP-IV inhibitor, caspase preoteaseinhibitor, an SGLT2 inhibitor, acetyl-CoA carboxylase inhibitor,sodium-bile acide cotransporter-inhibitor, TLR-4 antagonist, PPARalpha/delta agonist, a GLP-1 agonist, or a combination thereof; whereinthe FXR modulator is a compound having the structure:

or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

CCR2/CCR5 Antagonists:

Embodiments of CCR2/CCR5 antagonists used in combination with a firstagent that is an FXR inhibitor includes cenicriviroc (CVC), aplaviroc,vicriviroc5-({4-[(3S)-4-{2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine),maraviroc (e.g., 4,4′-difluorocyclohexylamide) and cochilioquinone ACaspase protease inhibitors:

Embodiments of caspase protease inhibitors used in combination with afirst agent that is an FXR inhibitor includes emricasan, Q-VD-Oph,DEVD-CHO, zVAD-FMK, Pralnacasan, and M867.

Acetyl-CoA Carboxylase Inhibitors:

Embodiments of acetyl-CoA carboxylase inhibitor used in combination witha first agent that is an FXR inhibitor includes(R)-2-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)-2-methylpropanoicacid,5-(tetradecyloxy)-2-furoic acid, Medica 16, and(3R)-1′-(9-anthracenylcarbonyl)[1,4′-bipiperidin]-3-yl]-4-morpholinyl-methanone.

Diacylglycerol Acyltransferase-1 Inhibitors:

Embodiments of diacylglycerol acyltransferase-1 inhibitors used incombination with a first agent that is an FXR inhibitor includespradigastat, VK5211, A 922500, amidepsine A, and amidepisne D.

Sodium-Bile Cotransporter Inhibitors:

Embodiments of sodium-bile cotransporter inhibitors used in combinationwith a first agent that is an FXR inhibitor includes volixibat, LJN 452,GSK2330672, AZD-7806, S-8921, AK-105, BARI-1741, SC-435 and SC-635.

TLR-4 Antagonist:

Embodiments of TLR-4 antagonists used in combination with a first agentthat is an FXR inhibitor includes JKB-121, amitriptyline, imipramine,naloxone, LPS-RS, cyclbenzprine, mianserin, naltrexone, propentofylline,ketotitfen, ibudilast, (+)-naltrexone, tapentradol, and eritoran.

PPAR Alpha/Delta Agonist:

Embodiments of PPAR alpha/delta agonists used in combination with afirst agent that is an FXR inhibitor includes GFT505, clofibrate,gemfibrozil, ciprofibrate, bezafibrate, and fenofibrate, GW501516,aleglitzar, muraglitazar, tesaglitazar, and saroglitazar.

DPP-IV Inhibitors:

Disclosed herein are DPP-IV inhibitors used in combination with a firstagent that is an FXR inhibitor. In some embodiments, the DPP-IVinhibitor is selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, and omarigliptin.

SGLT2 Inhibitors:

Disclosed herein are SGLT2 inhibitors used in combination with a firstagent that is an FXR inhibitor. In some embodiments, the SGLT2 inhibitoris selected from canagliflozin, empagliflozin, dapagliflozin,ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozinetabonate, and ertugliflozin.

ASK1 Inhibitors:

Disclosed herein are ASK1 inhibitors used in combination with a firstagent that is an FXR inhibitor. In some embodiments, the ASK1 inhibitoris selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide), and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride).

In some embodiments, the ASK1 inhibitor is selected from a compounddisclosed in any of the following publications: WO2008/016131;EP2058309, US2010/0029619, WO2016/49069, US2011/0009410, US2013/0197037,US2013/0197037, US201410179663, and US201410018370; each of which isincorporated by reference in their entirety.

GLP-1 Agonists:

Disclosed herein are GLP-1 agonists used in combination with a firstagent that is an FXR inhibitor. In some embodiments, the GLP-1 agonistis selected from exenatide, liraglutide, lixisenatide, albiglutide,dulaglutide, taspoglutide, and semaglutide.

Further Forms of Compounds Disclosed Herein Isomers

Furthermore, in some embodiments, the compounds described herein existas geometric isomers. In some embodiments, the compounds describedherein possess one or more double bonds. The compounds presented hereininclude all cis, trans, syn, anti, entgegen (E), and zusammen (Z)isomers as well as the corresponding mixtures thereof. In somesituations, compounds exist as tautomers. The compounds described hereininclude all possible tautomers within the formulas described herein.

In some situations, the compounds described herein possess one or morechiral centers and each center exists in the R configuration, or Sconfiguration. In some embodiments, the compounds described hereinpossess three chiral centers and each center exists in the Rconfiguration, or S configuration. In some embodiments, the compoundsdescribed herein possess four chiral centers and each center exists inthe R configuration, or S configuration. In some embodiments, thecompounds described herein include all diastereomeric, enantiomeric, andepimeric forms as well as the corresponding mixtures thereof. Inadditional embodiments of the compounds and methods provided herein,mixtures of enantiomers and/or diastereoisomers, resulting from a singlepreparative step, combination, or interconversion are useful for theapplications described herein. In some embodiments, the compoundsdescribed herein are prepared as their individual stereoisomers byreacting a racemic mixture of the compound with an optically activeresolving agent to form a pair of diastereoisomeric compounds,separating the diastereomers and recovering the optically pureenantiomers. In some embodiments, dissociable complexes are preferred(e.g., crystalline diastereomeric salts). In some embodiments, thediastereomers have distinct physical properties (e.g., melting points,boiling points, solubilities, reactivity, etc.) and are separated bytaking advantage of these dissimilarities. In some embodiments, thediastereomers are separated by chiral chromatography, or preferably, byseparation/resolution techniques based upon differences in solubility.In some embodiments, the optically pure enantiomer is then recovered,along with the resolving agent, by any practical means that would notresult in racemization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that areincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and pharmaceuticallyacceptable salts, esters, solvate, hydrates or derivatives thereof whichcontain the aforementioned isotopes and/or other isotopes of other atomsare within the scope of this invention. Certain isotopically-labeledcompounds, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i. e., ³H and carbon-14, i. e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavy isotopes such asdeuterium, i.e., ²H, produces certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements. In some embodiments, theisotopically labeled compounds, pharmaceutically acceptable salt, ester,solvate, hydrate or derivative thereof is prepared by any suitablemethod.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds of the invention, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Solvates

In some embodiments, the compounds described herein exist as solvates.The invention provides for methods of treating diseases by administeringsuch solvates. The invention further provides for methods of treatingdiseases by administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein are conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein are conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran ormethanol. In addition, the compounds provided herein exist in unsolvatedas well as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Combination Treatment

In some embodiments, the compounds disclosed herein are used incombination for the treatment of a disease, disorder or condition in amammal that would benefit from combined FXR modulation and DPP-IVinhibition. In some embodiments, the compounds disclosed herein are usedin combination for the treatment of a disease, disorder or condition ina mammal that would benefit from combined FXR modulation and SGLT2inhibition. In some embodiments, the compounds disclosed herein are usedin combination for the treatment of a disease, disorder or condition ina mammal that would benefit from combined FXR modulation and ASK1inhibition. In some embodiments, the compounds disclosed herein are usedin combination for the treatment of a disease, disorder or condition ina mammal that would benefit from combined FXR modulation and GLP-1modulation.

Disclosed herein, are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is a CCR2/CCR5antagonist.

Disclosed herein, are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is an ASK1 inhibitor.

Disclosed herein, are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is a DPP-IV inhibitor.

Disclosed herein, are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is a caspase proteaseinhibitor.

Disclosed herein, are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is an SGLT2 inhibitor.

Disclosed herein, are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is an acetyl-CoAcarboxylase inhibitor.

Disclosed herein, are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is a diacylglycerolacyltransferase-1 inhibitor.

Disclosed herein are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is a CCR2/CCR5antagonist selected from the group consisting of cenicriviroc (CVC),aplaviroc, vicriviroc5-({4-[(3S)-4-{2-methoxy-1-[4-(trifluoromethyl)phenyl]ethyl}-3-methylpiperazin-1-yl]-4-methylpiperidin-1-yl}carbonyl)-4,6-dimethylpyrimidine),maraviroc (e.g., 4,4′-difluorocyclohexylamide), and cochilioquinone A.

Disclosed herein, are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is a GLP-1 agonist.

In some embodiments, two second agents are co-administered with thefirst agent that is an FXR modulator. In some embodiments, the twosecond agents co-administered with a first agent that is an FXRmodulator are a DPP-IV inhibitor and an SGLT2 inhibitor. In someembodiments, the two second agents co-administered with a first agentthat is an FXR modulator are a DPP-IV inhibitor and an ASK1 inhibitor.In some embodiments, the two second agents co-administered with a firstagent that is an FXR modulator are a DPP-IV inhibitor and a GLP-1agonist. In some embodiments, the two second agents co-administered witha first agent that is an FXR modulator are an SGLT2 inhibitor and anASK1 inhibitor. In some embodiments, the two second agentsco-administered with a first agent that is an FXR modulator are an SGLT2inhibitor and a GLP-1 agonist. In some embodiments, the two secondagents co-administered with a first agent that is an FXR modulator arean ASK1 inhibitor and a GLP-1 agonist.

In some embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from combined FXR modulationand DPP-IV inhibition comprising administering compounds disclosedherein, wherein the disease, disorder or condition in a mammal isselected from nonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis, obesity, diabetic nephropathy and nephrotic syndrome. Insome embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from combined FXR modulationand DPP-IV inhibition comprising administering compounds disclosedherein, wherein the disease, disorder or condition in a mammal isnonalcoholic steatohepatitis (NASH). In some embodiments, is a method of(a) modulating FXR activity comprising contacting FXR, or portionthereof, with an FXR modulator disclosed herein and (b) inhibitingDPP-IV activity comprising contacting DPP-IV, or a portion thereof, witha DPP-IV inhibitor disclosed herein. In some embodiments, the compoundof FXR modulator is an FXR agonist. In some embodiments, the FXRmodulator is an FXR partial agonist. In some embodiments, the FXRmodulator is an FXR antagonist. In some embodiments, the disease,disorder or condition in a mammal that would benefit from (a) FXRmodulation and (b) DPP-IV inhibition is selected from nonalcoholicsteatohepatitis (NASH), hyperlipidemia, hypercholesterolemia,hypertriglyceridemia, dyslipidemia, lipodystrophy, atherosclerosis,atherosclerotic disease, atherosclerotic disease events, atheroscleroticcardiovascular disease, Syndrome X, diabetes mellitus, type II diabetes,insulin insensitivity, hyperglycemia, cholestasis, obesity, diabeticnephropathy and nephrotic syndrome.

In some embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from combined FXR modulationand SGLT2 inhibition comprising administering compounds disclosedherein, wherein the disease, disorder or condition in a mammal isselected from nonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis, obesity, diabetic nephropathy and nephrotic syndrome. Insome embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from combined FXR modulationand SGLT2 inhibition comprising administering compounds disclosedherein, wherein the disease, disorder or condition in a mammal isnonalcoholic steatohepatitis (NASH). In some embodiments, is a method of(a) modulating FXR activity comprising contacting FXR, or portionthereof, with an FXR modulator disclosed herein and (b) inhibiting SGLT2activity comprising contacting SGLT2, or a portion thereof, with anSGLT2 inhibitor disclosed herein. In some embodiments, the compound ofFXR modulator is an FXR agonist. In some embodiments, the FXR modulatoris an FXR partial agonist. In some embodiments, the FXR modulator is anFXR antagonist. In some embodiments, the disease, disorder or conditionin a mammal that would benefit from (a) FXR modulation and (b) SGLT2inhibition is selected from nonalcoholic steatohepatitis (NASH),hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease,atherosclerotic disease events, atherosclerotic cardiovascular disease,Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity,hyperglycemia, cholestasis, obesity, diabetic nephropathy and nephroticsyndrome.

In some embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from combined FXR modulationand ASK1 inhibition comprising administering compounds disclosed herein,wherein the disease, disorder or condition in a mammal is selected fromnonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis, obesity, diabetic nephropathy and nephrotic syndrome. Insome embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from combined FXR modulationand ASK1 inhibition comprising administering compounds disclosed herein,wherein the disease, disorder or condition in a mammal is nonalcoholicsteatohepatitis (NASH). In some embodiments, is a method of (a)modulating FXR activity comprising contacting FXR, or portion thereof,with an FXR modulator disclosed herein and (b) inhibiting ASK1 activitycomprising contacting ASK1, or a portion thereof, with a ASK1 inhibitordisclosed herein. In some embodiments, the compound of FXR modulator isan FXR agonist. In some embodiments, the FXR modulator is an FXR partialagonist. In some embodiments, the FXR modulator is an FXR antagonist. Insome embodiments, the disease, disorder or condition in a mammal thatwould benefit from (a) FXR modulation and (b) ASK1 inhibition isselected from nonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis, obesity, diabetic nephropathy and nephrotic syndrome.

In some embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from combined FXR modulationand GLP-1 agonism comprising administering compounds disclosed herein,wherein the disease, disorder or condition in a mammal is selected fromnonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis, obesity, diabetic nephropathy and nephrotic syndrome. Insome embodiments, is a method of treating a disease, disorder orcondition in a mammal that would benefit from combined FXR modulationand GLP-1 agonism comprising administering compounds disclosed herein,wherein the disease, disorder or condition in a mammal is nonalcoholicsteatohepatitis (NASH). In some embodiments, is a method of (a)modulating FXR activity comprising contacting FXR, or portion thereof,with an FXR modulator disclosed herein and (b) inhibiting GLP-1 activitycomprising contacting GLP-1, or a portion thereof, with a GLP-1 agonistdisclosed herein. In some embodiments, the compound of FXR modulator isan FXR agonist. In some embodiments, the FXR modulator is an FXR partialagonist. In some embodiments, the FXR modulator is an FXR antagonist. Insome embodiments, the disease, disorder or condition in a mammal thatwould benefit from (a) FXR modulation and (b) GLP-1 agonism is selectedfrom nonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis, obesity, diabetic nephropathy and nephrotic syndrome.

Combination with DPP-IV Inhibitors:

Disclosed herein are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is a DPP-IV inhibitorselected from sitagliptin, saxagliptin, linagliptin, alogliptin,vildagliptin, gemigliptin, anagliptin, teneligliptin, trelagliptin,dutogliptin, and omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (I) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (I) and (b) asecond agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (I) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (I) and (b) asecond agent that is teneligliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (I) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (II) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (II) and (b) asecond agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (II) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (II) and (b) asecond agent that is teneligliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (II) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (III) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (III) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (III) and (b)a second agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (III) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (III) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (III) and (b)a second agent that is teneligliptin. In some embodiments, is a methodof treating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (III) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (III) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IV) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IV) and (b) asecond agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IV) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IV) and (b) asecond agent that is teneligliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IV) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (V) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (V) and (b) asecond agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (V) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (V) and (b) asecond agent that is teneligliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (V) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VI) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VI) and (b) asecond agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VI) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VI) and (b) asecond agent that is teneligliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VI) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VII) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VII) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VII) and (b)a second agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VII) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VII) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VII) and (b)a second agent that is teneligliptin. In some embodiments, is a methodof treating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VII) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VII) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VIII) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VIII) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VIII) and (b)a second agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VIII) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VIII) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VIII) and (b)a second agent that is teneligliptin. In some embodiments, is a methodof treating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VIII) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VIII) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IX) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IX) and (b) asecond agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IX) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IX) and (b) asecond agent that is teneligliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IX) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (X) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (X) and (b) asecond agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (X) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (X) and (b) asecond agent that is teneligliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (X) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XI) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XI) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XI) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (XI) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XI) and (b) asecond agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XI) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XI) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (XI) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XI) and (b) asecond agent that is teneligliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XI) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XI) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (XI) and (b) a second agentthat is omarigliptin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that is aDPP-IV inhibitor selected from sitagliptin, saxagliptin, linagliptin,alogliptin, vildagliptin, gemigliptin, anagliptin, teneligliptin,trelagliptin, dutogliptin, or omarigliptin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XII) and (b) a second agent that is sitagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that issaxagliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (XII) and (b) a second agentthat is linagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XII) and (b)a second agent that is alogliptin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XII) and (b) a second agent that is vildagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that isgemigliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (XII) and (b) a second agentthat is anagliptin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XII) and (b)a second agent that is teneligliptin. In some embodiments, is a methodof treating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XII) and (b) a second agent that is trelagliptin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that isdutogliptin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (XII) and (b) a second agentthat is omarigliptin.

Combination with SGLT2 Inhibitors:

Disclosed herein are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is an SGLT2 inhibitorselected from canagliflozin, empagliflozin, dapagliflozin,ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozinetabonate, or ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (I) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (I) and (b) asecond agent that is ipragliflozin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (I) and (b) asecond agent that is remogliflozin etabonate. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (II) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (II) and (b) asecond agent that is ipragliflozin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (II) and (b) asecond agent that is remogliflozin etabonate. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (III) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (III) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (III) and (b)a second agent that is ipragliflozin. In some embodiments, is a methodof treating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (III) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (III) and (b)a second agent that is remogliflozin etabonate. In some embodiments, isa method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (III) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IV) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IV) and (b) asecond agent that is ipragliflozin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IV) and (b) asecond agent that is remogliflozin etabonate. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (V) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (V) and (b) asecond agent that is ipragliflozin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (V) and (b) asecond agent that is remogliflozin etabonate. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VI) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VI) and (b) asecond agent that is ipragliflozin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VI) and (b) asecond agent that is remogliflozin etabonate. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VII) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VII) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VII) and (b)a second agent that is ipragliflozin. In some embodiments, is a methodof treating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VII) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VII) and (b)a second agent that is remogliflozin etabonate. In some embodiments, isa method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VII) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VIII) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VIII) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VIII) and (b)a second agent that is ipragliflozin. In some embodiments, is a methodof treating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VIII) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VIII) and (b)a second agent that is remogliflozin etabonate. In some embodiments, isa method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VIII) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IX) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IX) and (b) asecond agent that is ipragliflozin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IX) and (b) asecond agent that is remogliflozin etabonate. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (X) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (X) and (b) asecond agent that is ipragliflozin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (X) and (b) asecond agent that is remogliflozin etabonate. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XI) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XI) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XI) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (XI) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XI) and (b) asecond agent that is ipragliflozin. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XI) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XI) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XI) and (b) asecond agent that is remogliflozin etabonate. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XI) and (b) a second agent that is ertugliflozin.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that is anSGLT2 inhibitor selected from canagliflozin, empagliflozin,dapagliflozin, ipragliflozin, tofogliflozin, sergliflozin etabonate,remogliflozin etabonate, or ertugliflozin. In some embodiments, is amethod of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XII) and (b) a second agent that is canagliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that isempagliflozin. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (XII) and (b) a second agentthat is dapagliflozin. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XII) and (b)a second agent that is ipragliflozin. In some embodiments, is a methodof treating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XII) and (b) a second agent that is tofogliflozin. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that issergliflozin etabonate. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XII) and (b)a second agent that is remogliflozin etabonate. In some embodiments, isa method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XII) and (b) a second agent that is ertugliflozin.

Combination with ASK1 Inhibitors:

Disclosed herein are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is an ASK1 inhibitorselected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride).

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (I) and (b) asecond agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is NQDI-1. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is ML365. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is MSC 2032964A. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that is TC ASK10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (II) and (b) asecond agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is NQDI-1. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is ML365. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is MSC 2032964A. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that is TCASK 10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (III) and (b)a second agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (III) and (b) a second agent that is NQDI-1. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that isML365. In some embodiments, is a method of treating a metabolic disorderin an individual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that is MSC2032964A. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (III) and (b) a second agentthat is TC ASK 10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IV) and (b) asecond agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is NQDI-1. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is ML365. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is MSC 2032964A. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that is TCASK 10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (V) and (b) asecond agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is NQDI-1. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is ML365. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is MSC 2032964A. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that is TC ASK10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VI) and (b) asecond agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is NQDI-1. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is ML365. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is MSC 2032964A. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that is TCASK 10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VII) and (b)a second agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VII) and (b) a second agent that is NQDI-1. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that isML365. In some embodiments, is a method of treating a metabolic disorderin an individual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that is MSC2032964A. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VII) and (b) a second agentthat is TC ASK 10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VIII) and (b)a second agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VIII) and (b) a second agent that is NQDI-1. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that isML365. In some embodiments, is a method of treating a metabolic disorderin an individual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that is MSC2032964A. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VIII) and (b) a second agentthat is TC ASK 10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IX) and (b) asecond agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is NQDI-1. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is ML365. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is MSC 2032964A. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that is TCASK 10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (X) and (b) asecond agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is NQDI-1. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is ML365. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is MSC 2032964A. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that is TC ASK10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XI) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XI) and (b) asecond agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XI) and (b) a second agent that is NQDI-1. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XI) and (b) a second agent that is ML365. In some embodiments,is a method of treating a metabolic disorder in an individual in needthereof, comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XI) and (b) a second agent that is MSC 2032964A. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XI) and (b) a second agent that is TCASK 10.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that is anASK1 inhibitor selected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide),and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride). In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (XII) and (b)a second agent that is selonsertib. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (XII) and (b) a second agent that is NQDI-1. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that isML365. In some embodiments, is a method of treating a metabolic disorderin an individual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (XII) and (b) a second agent that is MSC2032964A. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (XII) and (b) a second agentthat is TC ASK 10.

Disclosed herein are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is an ASK1 inhibitorselected from a compound disclosed in any of the following publications:WO2008/016131; EP2058309, US2010/0029619, WO2016/49069, U S2011/0009410,US 2013/0197037, US 2013/0197037 US 2014/0179663, and US2014/0018370.

Disclosed herein are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I), (II), (III), (IV), (V), (VI), (VII),(VIII), (IX), (X), (XI), or (XII); and (b) a second agent that is anASK1 inhibitor selected from a compound disclosed in any of thefollowing publications: WO2008/016131; EP2058309, US2010/0029619,WO2016/49069, US2011/0009410, US2013/0197037, US2013/0197037,US2014/0179663, and US2014/0018370.

Combination with GLP-1 Agonists:

Disclosed herein are methods of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator; and (b) a second agent that is a GLP-1 agonistselected from exenatide, liraglutide, lixisenatide, albiglutide,dulaglutide, taspoglutide, semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (I) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (I) and (b) asecond agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (I) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (I) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (I) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (I) and (b) asecond agent that is semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (II) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (II) and (b) asecond agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (II) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (II) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (II) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (II) and (b) asecond agent that is semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (III) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (III) and (b)a second agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (III) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (III) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (III) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (III) and (b)a second agent that is semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IV) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IV) and (b) asecond agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IV) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IV) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IV) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IV) and (b) asecond agent that is semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (V) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (V) and (b) asecond agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (V) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (V) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (V) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (V) and (b) asecond agent that is semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VI) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VI) and (b) asecond agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VI) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VI) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VI) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VI) and (b) asecond agent that is semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VII) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VII) and (b)a second agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VII) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VII) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VII) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VII) and (b)a second agent that is semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VIII) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VIII) and (b)a second agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (VIII) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (VIII) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (VIII) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (VIII) and (b)a second agent that is semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IX) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IX) and (b) asecond agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (IX) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (IX) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (IX) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (IX) and (b) asecond agent that is semaglutide.

In some embodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that is aGLP-1 agonist selected from exenatide, liraglutide, lixisenatide,albiglutide, dulaglutide, taspoglutide, semaglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that isexenatide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (X) and (b) a second agentthat is liraglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (X) and (b) asecond agent that is lixisenatide. In some embodiments, is a method oftreating a metabolic disorder in an individual in need thereof,comprising co-administering to the individual a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator ofFormula (X) and (b) a second agent that is albiglutide. In someembodiments, is a method of treating a metabolic disorder in anindividual in need thereof, comprising co-administering to theindividual a therapeutically effective amount of: (a) a first agent thatis an FXR modulator of Formula (X) and (b) a second agent that isdulaglutide. In some embodiments, is a method of treating a metabolicdisorder in an individual in need thereof, comprising co-administeringto the individual a therapeutically effective amount of: (a) a firstagent that is an FXR modulator of Formula (X) and (b) a second agentthat is taspoglutide. In some embodiments, is a method of treating ametabolic disorder in an individual in need thereof, comprisingco-administering to the individual a therapeutically effective amountof: (a) a first agent that is an FXR modulator of Formula (X) and (b) asecond agent that is semaglutide.

Pharmaceutical Compositions and Methods of Administration

Administration of FXR modulators as described herein can be in anypharmacological form including a therapeutically effective amount of anFXR modulator alone or in combination with a pharmaceutically acceptablecarrier.

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen.Additional details about suitable excipients for pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference for such disclosure.

A pharmaceutical composition, as used herein, refers to a mixture ofCompound 1, Compound 2, or Compound 3 described herein, with otherchemical components, such as carriers, stabilizers, diluents, dispersingagents, suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. In practicing the methods of treatment or use providedherein, therapeutically effective amounts of compounds described hereinare administered in a pharmaceutical composition to a mammal having adisease, disorder, or condition to be treated. In some embodiments, themammal is a human. A therapeutically effective amount can vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors.Compound 1, Compound 2, or Compound 3 can be used singly or incombination with one or more therapeutic agents as components ofmixtures (as in combination therapy).

The pharmaceutical formulations described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Moreover, the pharmaceutical compositions described herein,which include Compound 1, Compound 2, or Compound 3 described herein,can be formulated into any suitable dosage form, including but notlimited to, aqueous oral dispersions, liquids, gels, syrups, elixirs,slurries, suspensions, aerosols, controlled release formulations, fastmelt formulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

Dose administration can be repeated depending upon the pharmacokineticparameters of the dosage formulation and the route of administrationused.

It is especially advantageous to formulate compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used herein refers to physically discrete units suited asunitary dosages for the mammalian subjects to be treated; each unitcontaining a predetermined quantity of active compound calculated toproduce the desired therapeutic effect in association with the requiredpharmaceutical carrier. The specification for the dosage unit forms aredictated by and directly dependent on (a) the unique characteristics ofCompound 1, Compound 2, or Compound 3 and the particular therapeuticeffect to be achieved and (b) the limitations inherent in the art ofcompounding such an active compound for the treatment of sensitivity inindividuals. The specific dose can be readily calculated by one ofordinary skill in the art, e.g., according to the approximate bodyweight or body surface area of the patient or the volume of body spaceto be occupied. The dose will also be calculated dependent upon theparticular route of administration selected. Further refinement of thecalculations necessary to determine the appropriate dosage for treatmentis routinely made by those of ordinary skill in the art. Suchcalculations can be made without undue experimentation by one skilled inthe art in light of the Compound 1, Compound 2, or Compound 3 activitiesdisclosed herein in assay preparations of target cells. Exact dosagesare determined in conjunction with standard dose-response studies. Itwill be understood that the amount of the composition actuallyadministered will be determined by a practitioner, in the light of therelevant circumstances including the condition or conditions to betreated, the choice of composition to be administered, the age, weight,and response of the individual patient, the severity of the patient'ssymptoms, and the chosen route of administration.

Disclosed herein, in certain embodiments, are compositions for treatinga metabolic disorder in an individual in need thereof comprising a firstagent that is an FXR modulator and at least one second agent that is anCC2/CCR5 antagonist, ASK1 inhibitor, DPP-IV inhibitor, caspase preoteaseinhibitor, an SGLT2 inhibitor, acetyl-CoA carboxylase inhibitor,sodium-bile acide cotransporter-inhibitor, TLR-4 antagonist, PPARalpha/delta agonist, a GLP-1 agonist, or a combination thereof.Disclosed herein, in certain embodiments, are compositions for treatinga metabolic disorder in an individual in need thereof comprising a firstagent that is an FXR modulator and a second agent that is a DPP-IVinhibitor. Disclosed herein, in certain embodiments, are compositionsfor treating a metabolic disorder in an individual in need thereofcomprising a first agent that is an FXR modulator and a second agentthat is an SGLT2 inhibitor. Disclosed herein, in certain embodiments,are compositions for treating a metabolic disorder in an individual inneed thereof comprising a first agent that is an FXR modulator and asecond agent that is an ASK1 inhibitor. Disclosed herein, in certainembodiments, are compositions for treating a metabolic disorder in anindividual in need thereof comprising a first agent that is an FXRmodulator and a second agent that is a GLP-1 inhibitor.

Pharmaceutical compositions of a first agent that is an FXR modulatorand at least one second agent that is a DPP-IV inhibitor, an SGLT2inhibitor, an ASK1 inhibitor, a GLP-1 agonist, or a combination thereofare formulated in a conventional manner using one or morephysiologically acceptable carriers including excipients and auxiliarieswhich facilitate processing of the active compounds into preparationswhich can be used pharmaceutically. Proper formulation is dependent uponthe route of administration chosen. A summary of pharmaceuticalcompositions described herein is found, for example, in Remington: TheScience and Practice of Pharmacy, Tweentysecond Ed (PharmaceuticalPress, 2012); Hoover, John E., Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds.,Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; andPharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins 1999).

In some embodiments, the first agent that is an FXR modulator and secondagent that is a DPP-IV inhibitor are administered concurrently(simultaneously, essentially simultaneously, or withing the sametreatment protocol) or sequentially, depending upon the nature of thediseases, the condition of the patient, and the actual choice ofcompounds used.

Methods of Dosing and Treatment Regimens

In certain embodiments, the determination of the order ofadministration, and the number of repetitions of administration of eachtherapeutic agent during a treatment protocol, is based upon evaluationof the disease being treated and the condition of the patient.

The compounds described herein can be used in the preparation ofmedicaments for the modulation of FXR, or for the treatment of diseasesor conditions that would benefit, at least in part, from modulation ofFXR. In addition, a method for treating any of the diseases orconditions described herein in a subject in need of such treatment,involves administration of pharmaceutical compositions containing atleast one compound described herein, or a pharmaceutically acceptablesalt, or pharmaceutically acceptable solvate or hydrate thereof, intherapeutically effective amounts to said subject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician.

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. When used in a patient, effectiveamounts for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician. In certain embodiments, the first agent that is an FXRmodulator and the second agent are part of the same composition (fixedcombination). In some embodiments, the FXR modulator and the secondagent are administered as different compositions (non-fixedcombinations). In another embodiment, the FXR modulator is administeredprior to the second agent. In some embodiments, the DPP-IV inhibitor isadministered prior to the FXR modulator. As many of the disorders forwhich the compounds and compositions of the invention are useful intreating are chronic disorders, in one embodiment combination therapyinvolves alternating between administering an FXR modulator and a secondagent, e.g., to minimize the toxicity associated with a particular drug.The duration of administration of each drug or therapeutic agent can beone day, one week, one month, three months, six months, or a year.

In some embodiments, the initial administration of FXR modulator and thesecond agent are via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over 5 minutes toabout 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof.

The FXR modulator and the second agent should be administered as soon asis practicable after the onset of a disorder is detected or suspected,and for a length of time necessary for the treatment of the disease,such as, for example, from about 1 month to about 3 months, orcontinuously throughout the individual's life. The length of treatmentcan vary for each subject, and the length can be determined using theknown criteria. In some embodiments, the FXR modulator and the secondagent are administered for at least 2 weeks, between about 1 month toabout 5 years, or from about 1 month to about 3 years. In someembodiments, the FXR modulator and the second agent are administeredthroughout the individual's life.

Therapeutically effective amounts will depend on the severity and courseof the disorder, previous therapy, the patient's health status, weight,and response to the drugs, and the judgment of the treating physician.Prophylactically effective amounts depend on the patient's state ofhealth, weight, the severity and course of the disease, previoustherapy, response to the drugs, and the judgment of the treatingphysician.

In some embodiments, the FXR modulator and the second agent areadministered to the patient on a regular basis, e.g., three times a day,two times a day, once a day, every other day or every 3 days. In otherembodiments, the FXR modulator and the second agent are administered tothe patient on an intermittent basis, e.g., twice a day followed by oncea day followed by three times a day; or the first two days of everyweek; or the first, second and third day of a week. In some embodiments,intermittent dosing is as effective as regular dosing. In further oralternative embodiments, the FXR modulator and the second agent areadministered only when the patient exhibits a particular symptom, e.g.,the onset of pain, or the onset of a fever, or the onset of aninflammation, or the onset of a skin disorder. Dosing schedules of eachcompound may depend on the other or may be independent of the other.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisorder.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from 10%-100%,including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenanceregimen is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, of The FXR modulator and thesecond agent can be reduced, as a function of the symptoms, to a levelat which the individual's improved condition is retained. Individualscan, however, require intermittent treatment on a long-term basis uponany recurrence of symptoms.

The amount of the FXR modulator and the second agent are will varydepending upon factors such as the particular compound, disorder and itsseverity, the identity (e.g., weight) of the subject or host in need oftreatment, and is determined according to the particular circumstancessurrounding the case, including, e.g., the specific agents beingadministered, the routes of administration, and the subject or hostbeing treated. In general, however, doses employed for adult humantreatment will typically be in the range of 0.02-5000 mg per day.

In some embodiments, the effective dose of the FXR modulator is about 1mg to about 1500 mg, about 1 mg to about 1400 mg, about 1 mg to about1300 mg, about 1 mg to about 1200 mg, about 1 mg to about 1100 mg, about1 mg to about 1000 mg, 1 mg to about 900 mg, about 1 mg to about 800 mg,about 1 mg to about 700 mg. In some embodiments, the effective dose ofthe FXR modulator is about 1 mg to about 600 mg, about 1 mg to about 500mg, about 1 mg to about 400 mg, about 1 mg to about 300 mg, about 1 mgto about 200 mg, about 1 mg to about 100 mg, about 1 mg to about 90 mg,about 1 mg to about 80 mg, about 1 mg to about 70 mg, about 1 mg toabout 60 mg, about 1 mg to about 50 mg, about 1 mg to about 40 mg, about1 mg to about 30 mg, about 1 mg to about 20 mg, about 1 mg to about 10mg, or about 1 mg to about 5 mg.

In some embodiments, the effective dose of the FXR modulator is about 10mg to about 1500 mg, about 20 mg to about 1500 mg, about 30 mg to about1500 mg, about 40 mg to about 1500 mg, about 50 mg to about 1500 mg,about 60 mg to about 1500 mg, about 70 mg to about 1500 mg, about 80 mgto about 1500 mg, about 90 mg to about 1500 mg, about 100 mg to about1500 mg, about 200 mg to about 1500 mg, about 300 mg to about 1500 mg,about 400 mg to about 1500 mg, about 500 mg to about 1500 mg, about 600mg to about 1500 mg, about 700 mg to about 1500 mg, about 800 mg toabout 1500 mg, about 900 mg to about 1500 mg, about 1000 mg to about1500 mg, about 1100 mg to about 1500 mg, about 1200 mg to about 1500 mg,about 1300 mg to about 1500 mg, or about 1400 mg to about 1500 mg. Insome embodiments, the effective dose of the FXR modulator of Formula(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), or(XII) is about 10 mg to about 450 mg, about 10 mg to about 50 mg, about50 mg to about 100 mg, about 100 mg to about 200 mg, about 200 mg toabout 300 mg, or about 300 mg to about 450 mg. In some embodiments, theeffective dose of the FXR modulator of Formula (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is about 1 mg toabout 100 mg, about 1 mg to about 5 mg, about 5 mg to about 10 mg, about10 mg to about 25 mg, about 25 mg to about 50 mg, about 50 mg to about75 mg, or about 75 mg to about 100 mg. In some embodiments, theeffective dose of the FXR modulator of Formula (I), (II), (III), (IV),(V), (VI), (VII), (VIII), (IX), (X), (XI), or (XII) is about 10 mg toabout 250 mg, about 10 mg to about 50 mg, about 50 mg to about 100 mg,about 100 mg to about 150 mg, about 150 mg to about 200 mg, or about 200mg to about 250 mg. In some embodiments, the effective dose of the FXRmodulator of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII),(IX), (X), (XI), or (XII) is about 500 mg to about 1500 mg, about 500 mgto about 600 mg, about 600 mg to about 700 mg, about 700 mg to about 800mg, about 800 mg to about 900 mg, about 900 mg to about 1000 mg, about1000 mg to about 1200 mg, or about 1200 mg to about 1500 mg.

In some embodiments, the effective dose of the DPP-IV inhibitor is about1 mg to about 1000 mg. In some embodiments, the effective dose of theDPP-IV inhibitor is about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg,about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg,about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg,about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg,about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg,about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg,about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg,about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg,about 23.5 mg, about 24 mg, about 24.5 mg, about 25 mg, about 25.5 mg,about 26 mg, about 26.5 mg, about 27 mg, about 27.5 mg, about 28 mg,about 28.5 mg, about 29 mg, about 29.5 mg, about 30 mg, about 30.5 mg,about 31 mg, about 31.5 mg, about 32 mg, about 32.5 mg, about 33 mg,about 33.5 mg, about 34 mg, about 34.5 mg, about 35 mg, about 35.5 mg,about 36 mg, about 36.5 mg, about 37 mg, about 37.5 mg, about 38 mg,about 38.5 mg, about 39 mg, about 39.5 mg, about 40 mg, about 41 mg,about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg,about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg,about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg,about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg,about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg,about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 125 mg, about150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about800 mg, about 850 mg, about 900 mg, or about 950 mg, about 1000 mg. Incertain embodiments, any two of the doses in this paragraph may becombined to form a range of dosages included within the disclosure,e.g., the topical composition comprises from about 2 mg to about 100 mg,from about 10 mg to about 150 mg, from about 50 mg to about 200 mg, orfrom about 100 mg to about 300 mg.

In some embodiments, the effective dose of the SGLT2 inhibitor is about1 mg to about 1000 mg. In some embodiments, the effective dose of theSGLT2 inhibitor is about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg,about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg,about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg,about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg,about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg,about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg,about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg,about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg,about 23.5 mg, about 24 mg, about 24.5 mg, about 25 mg, about 25.5 mg,about 26 mg, about 26.5 mg, about 27 mg, about 27.5 mg, about 28 mg,about 28.5 mg, about 29 mg, about 29.5 mg, about 30 mg, about 30.5 mg,about 31 mg, about 31.5 mg, about 32 mg, about 32.5 mg, about 33 mg,about 33.5 mg, about 34 mg, about 34.5 mg, about 35 mg, about 35.5 mg,about 36 mg, about 36.5 mg, about 37 mg, about 37.5 mg, about 38 mg,about 38.5 mg, about 39 mg, about 39.5 mg, about 40 mg, about 41 mg,about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg,about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg,about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg,about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg,about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg,about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 125 mg, about150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about800 mg, about 850 mg, about 900 mg, or about 950 mg, about 1000 mg. Incertain embodiments, any two of the doses in this paragraph may becombined to form a range of dosages included within the disclosure,e.g., the topical composition comprises from about 2 mg to about 100 mg,from about 10 mg to about 150 mg, from about 50 mg to about 200 mg, orfrom about 100 mg to about 300 mg.

In some embodiments, the effective dose of the ASK1 inhibitor is about 1mg to about 1000 mg. In some embodiments, the effective dose of the ASK1inhibitor is about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg,about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, about 16 mg,about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg, about 18.5 mg,about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg, about 21 mg,about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg, about 23.5 mg,about 24 mg, about 24.5 mg, about 25 mg, about 25.5 mg, about 26 mg,about 26.5 mg, about 27 mg, about 27.5 mg, about 28 mg, about 28.5 mg,about 29 mg, about 29.5 mg, about 30 mg, about 30.5 mg, about 31 mg,about 31.5 mg, about 32 mg, about 32.5 mg, about 33 mg, about 33.5 mg,about 34 mg, about 34.5 mg, about 35 mg, about 35.5 mg, about 36 mg,about 36.5 mg, about 37 mg, about 37.5 mg, about 38 mg, about 38.5 mg,about 39 mg, about 39.5 mg, about 40 mg, about 41 mg, about 42 mg, about43 mg, about 44 mg, about 45 mg, about 46 mg, about 47 mg, about 48 mg,about 49 mg, about 50 mg, about 51 mg, about 52 mg, about 53 mg, about54 mg, about 55 mg, about 56 mg, about 57 mg, about 58 mg, about 59 mg,about 60 mg, about 61 mg, about 62 mg, about 63 mg, about 64 mg, about65 mg, about 66 mg, about 67 mg, about 68 mg, about 69 mg, about 70 mg,about 71 mg, about 72 mg, about 73 mg, about 74 mg, about 75 mg, about76 mg, about 77 mg, about 78 mg, about 79 mg, about 80 mg, about 81 mg,about 82 mg, about 83 mg, about 84 mg, about 85 mg, about 86 mg, about87 mg, about 88 mg, about 89 mg, about 90 mg, about 91 mg, about 92 mg,about 93 mg, about 94 mg, about 95 mg, about 96 mg, about 97 mg, about98 mg, about 99 mg, about 100 mg, about 125 mg, about 150 mg, about 175mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425mg, about 450 mg, about 475 mg, about 500 mg, about 550 mg, about 600mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850mg, about 900 mg, or about 950 mg, about 1000 mg. In certainembodiments, any two of the doses in this paragraph may be combined toform a range of dosages included within the disclosure, e.g., thetopical composition comprises from about 2 mg to about 100 mg, fromabout 10 mg to about 150 mg, from about 50 mg to about 200 mg, or fromabout 100 mg to about 300 mg.

In some embodiments, the effective dose of the GLP-1 agonist is about 1mg to about 1000 mg. In some embodiments, the effective dose of theGLP-1 agonist is about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg,about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg,about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg,about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg,about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg,about 16 mg, about 16.5 mg, about 17 mg, about 17.5 mg, about 18 mg,about 18.5 mg, about 19 mg, about 19.5 mg, about 20 mg, about 20.5 mg,about 21 mg, about 21.5 mg, about 22 mg, about 22.5 mg, about 23 mg,about 23.5 mg, about 24 mg, about 24.5 mg, about 25 mg, about 25.5 mg,about 26 mg, about 26.5 mg, about 27 mg, about 27.5 mg, about 28 mg,about 28.5 mg, about 29 mg, about 29.5 mg, about 30 mg, about 30.5 mg,about 31 mg, about 31.5 mg, about 32 mg, about 32.5 mg, about 33 mg,about 33.5 mg, about 34 mg, about 34.5 mg, about 35 mg, about 35.5 mg,about 36 mg, about 36.5 mg, about 37 mg, about 37.5 mg, about 38 mg,about 38.5 mg, about 39 mg, about 39.5 mg, about 40 mg, about 41 mg,about 42 mg, about 43 mg, about 44 mg, about 45 mg, about 46 mg, about47 mg, about 48 mg, about 49 mg, about 50 mg, about 51 mg, about 52 mg,about 53 mg, about 54 mg, about 55 mg, about 56 mg, about 57 mg, about58 mg, about 59 mg, about 60 mg, about 61 mg, about 62 mg, about 63 mg,about 64 mg, about 65 mg, about 66 mg, about 67 mg, about 68 mg, about69 mg, about 70 mg, about 71 mg, about 72 mg, about 73 mg, about 74 mg,about 75 mg, about 76 mg, about 77 mg, about 78 mg, about 79 mg, about80 mg, about 81 mg, about 82 mg, about 83 mg, about 84 mg, about 85 mg,about 86 mg, about 87 mg, about 88 mg, about 89 mg, about 90 mg, about91 mg, about 92 mg, about 93 mg, about 94 mg, about 95 mg, about 96 mg,about 97 mg, about 98 mg, about 99 mg, about 100 mg, about 125 mg, about150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about800 mg, about 850 mg, about 900 mg, or about 950 mg, about 1000 mg. Incertain embodiments, any two of the doses in this paragraph may becombined to form a range of dosages included within the disclosure,e.g., the topical composition comprises from about 2 mg to about 100 mg,from about 10 mg to about 150 mg, from about 50 mg to about 200 mg, orfrom about 100 mg to about 300 mg.

It is understood that a medical professional will determine the dosageregimen in accordance with a variety of factors. These factors includethe age, weight, sex, diet, and medical condition of the subject. Theamount of a given agent that will correspond to such an amount will varydepending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be determined in amanner recognized in the field according to the particular circumstancessurrounding the case, including, e.g., the specific agent beingadministered, the route of administration, the condition being treated,and the subject or host being treated. In general, however, dosesemployed for adult human treatment will typically be in the range ofabout 0.01 mg per day to about 5000 mg per day, in some embodiments,about 1 mg per day to about 1500 mg per day. The desired dose mayconveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

In some embodiments, a pharmaceutical composition, refers to a mixtureof an FXR modulator and a second agent with other chemical components,such as carriers, stabilizers, diluents, dispersing agents, suspendingagents, thickening agents, and/or excipients. In some embodiments, apharmaceutical composition refers to an FXR modulator with otherchemical components, such as carriers, stabilizers, diluents, dispersingagents, suspending agents, thickening agents, and/or excipients. In someembodiments, a pharmaceutical composition refers to a DPP-IV inhibitorwith other chemical components, such as carriers, stabilizers, diluents,dispersing agents, suspending agents, thickening agents, and/orexcipients. In some embodiments, a pharmaceutical composition refers toan SGLT2 inhibitor with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. In some embodiments, a pharmaceuticalcomposition refers to a ASK1 inhibitor with other chemical components,such as carriers, stabilizers, diluents, dispersing agents, suspendingagents, thickening agents, and/or excipients. In some embodiments, apharmaceutical composition refers to a GLP-1 agonist with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients.

Pharmaceutical compositions are optionally manufactured in aconventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

In certain embodiments, compositions may also include one or more pHadjusting agents or buffering agents, including acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

In other embodiments, compositions may also include one or more salts inan amount required to bring osmolality of the composition into anacceptable range. Such salts include those having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

The pharmaceutical formulations described herein are administered by anysuitable administration route, including but not limited to, oral,parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal,buccal, topical, rectal, or transdermal administration routes.

The pharmaceutical compositions described herein are formulated into anysuitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions andthe like, for oral ingestion by an individual to be treated, solid oraldosage forms, aerosols, controlled release formulations, fast meltformulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations. In some embodiments, thecompositions are formulated into capsules. In some embodiments, thecompositions are formulated into solutions (for example, for IVadministration).

The pharmaceutical compositions described herein are formulated intounit dosage forms suitable for single administration of precise dosages.In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or both compounds. The unitdosage may be in the form of a package containing discrete quantities ofthe formulation. Non-limiting examples are packaged tablets or capsules,and powders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The pharmaceutical solid dosage forms described herein optionallyinclude a compound described herein and one or more pharmaceuticallyacceptable additives such as a compatible carrier, binder, fillingagent, suspending agent, flavoring agent, sweetening agent,disintegrating agent, dispersing agent, surfactant, lubricant, colorant,diluent, solubilizer, moistening agent, plasticizer, stabilizer,penetration enhancer, wetting agent, anti-foaming agent, antioxidant,preservative, or one or more combination thereof.

In still other aspects, using standard coating procedures, such as thosedescribed in Remington's Pharmaceutical Sciences, 20th Edition (2000), afilm coating is provided around the compositions. In some embodiments,the compositions are formulated into particles (for example foradministration by capsule) and some or all of the particles are coated.In some embodiments, the compositions are formulated into particles (forexample for administration by capsule) and some or all of the particlesare microencapsulated. In some embodiments, the compositions areformulated into particles (for example for administration by capsule)and some or all of the particles are not microencapsulated and areuncoated.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include mercury-containing substances such as merfen andthiomersal; stabilized chlorine dioxide; and quaternary ammoniumcompounds such as benzalkonium chloride, cetyltrimethylammonium bromideand cetylpyridinium chloride.

“Antifoaming agents” reduce foaming during processing which can resultin coagulation of aqueous dispersions, bubbles in the finished film, orgenerally impair processing. Exemplary anti-foaming agents includesilicon emulsions or sorbitan sesquoleate.

“Antioxidants” include, for example, butylated hydroxytoluene (BHT),sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. Incertain embodiments, antioxidants enhance chemical stability whererequired.

Formulations described herein may benefit from antioxidants, metalchelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v, polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

“Binders” impart cohesive qualities and include, e.g., alginic acid andsalts thereof; cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

A “carrier” or “carrier materials” include any commonly used excipientsin pharmaceutics and should be selected on the basis of compatibilitywith compounds disclosed herein, and the release profile properties ofthe desired dosage form. Exemplary carrier materials include, e.g.,binders, suspending agents, disintegration agents, filling agents,surfactants, solubilizers, stabilizers, lubricants, wetting agents,diluents, and the like. “Pharmaceutically compatible carrier materials”may include, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, polyvinylpyrrollidone (PVP), cholesterol,cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid,phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassiumphosphate, cellulose and cellulose conjugates, sugars sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, and the like. See, e.g., Remington: The Science and Practice ofPharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995);Hoover, John E., Remington's Pharmaceutical Sciences, Mack PublishingCo., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds.,Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; andPharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed.(Lippincott Williams & Wilkins 1999).

“Dispersing agents,” and/or “viscosity modulating agents” includematerials that control the diffusion and homogeneity of a drug throughliquid media or a granulation method or blend method. In someembodiments, these agents also facilitate the effectiveness of a coatingor eroding matrix. Exemplary diffusion facilitators/dispersing agentsinclude, e.g., hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and thecarbohydrate-based dispersing agents such as, for example, hydroxypropylcelluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)),polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetatecopolymer (S-630), polyethylene glycol, e.g., the polyethylene glycolcan have a molecular weight of about 300 to about 6000, or about 3350 toabout 4000, or about 7000 to about 5400, sodium carboxymethylcellulose,methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g.,gum tragacanth and gum acacia, guar gum, xanthans, including xanthangum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodiumalginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitanmonolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates,chitosans and combinations thereof. Plasticizers such as cellulose ortriethyl cellulose can also be used as dispersing agents. Dispersingagents particularly useful in liposomal dispersions and self-emulsifyingdispersions are dimyristoyl phosphatidyl choline, natural phosphatidylcholine from eggs, natural phosphatidyl glycerol from eggs, cholesteroland isopropyl myristate.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution. In certain embodiments,diluents increase bulk of the composition to facilitate compression orcreate sufficient bulk for homogenous blend for capsule filling. Suchcompounds include e.g., lactose, starch, mannitol, sorbitol, dextrose,microcrystalline cellulose such as Avicel®; dibasic calcium phosphate,dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;anhydrous lactose, spray-dried lactose; pregelatinized starch,compressible sugar, such as Di-Pac® (Amstar); mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, confectioner's sugar; monobasiccalcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactatetrihydrate, dextrates; hydrolyzed cereal solids, amylose; powderedcellulose, calcium carbonate; glycine, kaolin; mannitol, sodiumchloride; inositol, bentonite, and the like.

The term “disintegrate” includes both the dissolution and dispersion ofthe dosage form when contacted with gastrointestinal fluid.“Disintegration agents or disintegrants” facilitate the breakup ordisintegration of a substance. Examples of disintegration agents includea starch, e.g., a natural starch such as corn starch or potato starch, apregelatinized starch such as National 1551 or Amijel®, or sodium starchglycolate such as Promogel® or Explotab®, a cellulose such as a woodproduct, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101,Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, MingTia®, and Solka-Floc®, methylcellulose, croscarmellose, or across-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

“Drug absorption” or “absorption” typically refers to the process ofmovement of drug from site of administration of a drug across a barrierinto a blood vessel or the site of action, e.g., a drug moving from thegastrointestinal tract into the portal vein or lymphatic system.

An “enteric coating” is a substance that remains substantially intact inthe stomach but dissolves and releases the drug in the small intestineor colon. Generally, the enteric coating comprises a polymeric materialthat prevents release in the low pH environment of the stomach but thationizes at a higher pH, typically a pH of 6 to 7, and thus dissolvessufficiently in the small intestine or colon to release the active agenttherein.

“Erosion facilitators” include materials that control the erosion of aparticular material in gastrointestinal fluid. Erosion facilitators aregenerally known to those of ordinary skill in the art. Exemplary erosionfacilitators include, e.g., hydrophilic polymers, electrolytes,proteins, peptides, and amino acids. Combinations of one or more erosionfacilitator with one or more diffusion facilitator can also be used inthe present compositions.

“Filling agents” include compounds such as lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol,mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

“Flavoring agents” and/or “sweeteners” useful in the formulationsdescribed herein, include, e.g., acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,wintergreen, xylitol, or any combination of these flavoring ingredients,e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon,chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus,orange-cream, vanilla-mint, and mixtures thereof.

“Lubricants” and “glidants” are compounds that prevent, reduce orinhibit adhesion or friction of materials. Exemplary lubricants include,e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, ahydrocarbon such as mineral oil, or hydrogenated vegetable oil such ashydrogenated soybean oil (Sterotex®), higher fatty acids and theiralkali-metal and alkaline earth metal salts, such as aluminum, calcium,magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes,Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol (e.g., PEG-4000) or amethoxypolyethylene glycol such as Carbowax™, sodium oleate, sodiumbenzoate, glyceryl behenate, polyethylene glycol, magnesium or sodiumlauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, a starchsuch as corn starch, silicone oil, a surfactant, and the like.

“Plasticizers” are compounds used to soften the microencapsulationmaterial or film coatings to make them less brittle. Suitableplasticizers include, e.g., polyethylene glycols such as PEG 300, PEG400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propyleneglycol, oleic acid, triethyl cellulose and triacetin. In someembodiments, plasticizers can also function as dispersing agents orwetting agents.

“Solubilizers” include compounds such as triacetin, triethylcitrate,ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate,vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropylalcohol, cholesterol, bile salts, polyethylene glycol 200-600,glycofurol, transcutol, propylene glycol, and dimethyl isosorbide andthe like.

“Stabilizers” include compounds such as any antioxidation agents,buffers, acids, preservatives and the like.

“Steady state,” as used herein, is when the amount of drug administeredis equal to the amount of drug eliminated within one dosing intervalresulting in a plateau or constant plasma drug exposure.

“Suspending agents” include compounds such as polyvinylpyrrolidone,e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g.,the polyethylene glycol can have a molecular weight of about 300 toabout 6000, or about 3350 to about 4000, or about 7000 to about 5400,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Someother surfactants include polyoxyethylene fatty acid glycerides andvegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40. In some embodiments, surfactants may be included toenhance physical stability or for other purposes.

“Viscosity enhancing agents” include, e.g., methyl cellulose, xanthangum, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetatestearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinylalcohol, alginates, acacia, chitosans and combinations thereof.

“Wetting agents” include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate,sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium saltsand the like.

It should be appreciated that there is considerable overlap betweenadditives used in the solid dosage forms described herein. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in solid dosageforms described herein. The amounts of such additives can be readilydetermined by one skilled in the art, according to the particularproperties desired.

Conventional pharmacological techniques include, e.g., one or acombination of methods: (1) dry mixing, (2) direct compression, (3)milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6)fusion. See, e.g., Lachman et al., The Theory and Practice of IndustrialPharmacy (1986). Other methods include, e.g., spray drying, pan coating,melt granulation, granulation, fluidized bed spray drying or coating(e.g., wurster coating), tangential coating, top spraying, tableting,extruding and the like.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In other embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the FXR modulator in combination with or separately from asecond agent, from the formulation. In other embodiments, the filmcoating aids in patient compliance (e.g., Opadry® coatings or sugarcoating). Film coatings including Opadry® typically range from about 1%to about 3% of the tablet weight. In other embodiments, the compressedtablets include one or more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compounds described herein, inside of a capsule. Insome embodiments, the formulations (non-aqueous suspensions andsolutions) are placed in a soft gelatin capsule. In other embodiments,the formulations are placed in standard gelatin capsules or non-gelatincapsules such as capsules comprising HPMC. In other embodiments, theformulation is placed in a sprinkle capsule, wherein the capsule may beswallowed whole or the capsule may be opened and the contents sprinkledon food prior to eating. In some embodiments, the therapeutic dose issplit into multiple (e.g., two, three, or four) capsules. In someembodiments, the entire dose of the formulation is delivered in acapsule form.

In various embodiments, the particles of the compounds described hereinand one or more excipients are dry blended and compressed into a mass,such as a tablet, having a hardness sufficient to provide apharmaceutical composition that substantially disintegrates within lessthan about 30 minutes, less than about 35 minutes, less than about 40minutes, less than about 45 minutes, less than about 50 minutes, lessthan about 55 minutes, or less than about 60 minutes, after oraladministration, thereby releasing the formulation into thegastrointestinal fluid.

In another aspect, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with the compounds described herein, whichsufficiently isolate the compounds from other non-compatible excipients.Materials compatible with compounds of any of the FXR modulators and thesecond agent, are those that delay the release of the compounds of anyof the FXR modulator and the second agent, in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds described herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® 5100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® 512.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In still other embodiments, plasticizers such as polyethylene glycols,e.g., PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800,stearic acid, propylene glycol, oleic acid, and triacetin areincorporated into the microencapsulation material. In other embodiments,the microencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In yet other embodiments, the microencapsulation material isKlucel. In still other embodiments, the microencapsulation material ismethocel.

Microencapsulated compounds of the compounds described herein may beformulated by methods known by one of ordinary skill in the art. Suchknown methods include, e.g., spray drying processes, spinningdisk-solvent processes, hot melt processes, spray chilling methods,fluidized bed, electrostatic deposition, centrifugal extrusion,rotational suspension separation, polymerization at liquid-gas orsolid-gas interface, pressure extrusion, or spraying solvent extractionbath. In addition to these, several chemical techniques, e.g., complexcoacervation, solvent evaporation, polymer-polymer incompatibility,interfacial polymerization in liquid media, in situ polymerization,in-liquid drying, and desolvation in liquid media could also be used.Furthermore, other methods such as roller compaction,extrusion/spheronization, coacervation, or nanoparticle coating may alsobe used.

In one embodiment, the particles of the compounds described herein aremicroencapsulated prior to being formulated into one of the above forms.In still another embodiment, some or most of the particles are coatedprior to being further formulated by using standard coating procedures,such as those described in Remington's Pharmaceutical Sciences, 20thEdition (2000).

In still other embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When salts of the compositions describedherein are added to water, the acids and the base react to liberatecarbon dioxide gas, thereby causing “effervescence.” Examples ofeffervescent salts include, e.g., the following ingredients: sodiumbicarbonate or a mixture of sodium bicarbonate and sodium carbonate,citric acid and/or tartaric acid. Any acid-base combination that resultsin the liberation of carbon dioxide can be used in place of thecombination of sodium bicarbonate and citric and tartaric acids, as longas the ingredients were suitable for pharmaceutical use and result in apH of about 6.0 or higher.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. It is expected that anyanionic polymer exhibiting a pH-dependent solubility profile can be usedas an enteric coating in the methods and compositions described hereinto achieve delivery to the lower gastrointestinal tract. In someembodiments the polymers described herein are anionic carboxylicpolymers. In other embodiments, the polymers and compatible mixturesthereof, and some of their properties, include, but are not limited to:

Shellac, also called purified lac, a refined product obtained from theresinous secretion of an insect. This coating dissolves in media of pH>7;

Acrylic polymers. The performance of acrylic polymers (primarily theirsolubility in biological fluids) can vary based on the degree and typeof substitution. Examples of suitable acrylic polymers includemethacrylic acid copolymers and ammonium methacrylate copolymers. TheEudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available assolubilized in organic solvent, aqueous dispersion, or dry powders. TheEudragit series RL, NE, and RS are insoluble in the gastrointestinaltract but are permeable and are used primarily for colonic targeting.The Eudragit series E dissolve in the stomach. The Eudragit series L,L-30D and S are insoluble in stomach and dissolve in the intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are:ethyl cellulose; reaction mixtures of partial acetate esters ofcellulose with phthalic anhydride. The performance can vary based on thedegree and type of substitution. Cellulose acetate phthalate (CAP)dissolves in pH >6. Aquateric (FMC) is an aqueous based system and is aspray dried CAP psuedolatex with particles <1 μm. Other components inAquateric can include pluronics, Tweens, and acetylated monoglycerides.Other suitable cellulose derivatives include: cellulose acetatetrimellitate (Eastman); methylcellulose (Pharmacoat, Methocel);hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetatesuccinate (e.g., AQOAT (Shin Etsu)). The performance can vary based onthe degree and type of substitution. For example, HPMCP such as, HP-50,HP-55, HP-555, HP-55F grades are suitable. The performance can varybased on the degree and type of substitution. For example, suitablegrades of hydroxypropylmethylcellulose acetate succinate include, butare not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF),which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.These polymers are offered as granules, or as fine powders for aqueousdispersions; Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves inpH >5, and it is much less permeable to water vapor and gastric fluids.

In some embodiments, the coating can, and usually does, contain aplasticizer and possibly other coating excipients such as colorants,talc, and/or magnesium stearate, which are well known in the art.Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin(glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate,acetylated monoglycerides, glycerol, fatty acid esters, propyleneglycol, and dibutyl phthalate. In particular, anionic carboxylic acrylicpolymers usually will contain 10-25% by weight of a plasticizer,especially dibutyl phthalate, polyethylene glycol, triethyl citrate andtriacetin. Conventional coating techniques such as spray or pan coatingare employed to apply coatings. The coating thickness must be sufficientto ensure that the oral dosage form remains intact until the desiredsite of topical delivery in the intestinal tract is reached.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants(e.g., carnuba wax or PEG) may be added to the coatings besidesplasticizers to solubilize or disperse the coating material, and toimprove coating performance and the coated product.

In other embodiments, the formulations described herein, which includethe compounds described herein, are delivered using a pulsatile dosageform. A pulsatile dosage form is capable of providing one or moreimmediate release pulses at predetermined time points after a controlledlag time or at specific sites. Many other types of controlled releasesystems known to those of ordinary skill in the art and are suitable foruse with the formulations described herein. Examples of such deliverysystems include, e.g., polymer-based systems, such as polylactic andpolyglycolic acid, plyanhydrides and polycaprolactone; porous matrices,nonpolymer-based systems that are lipids, including sterols, such ascholesterol, cholesterol esters and fatty acids, or neutral fats, suchas mono-, di- and triglycerides; hydrogel release systems; silasticsystems; peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2^(nd)Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509,5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410,5,977,175, 6,465,014 and 6,932,983.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of the compounds described herein and at least onedispersing agent or suspending agent for oral administration to asubject. The formulations may be a powder and/or granules forsuspension, and upon admixture with water, a substantially uniformsuspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2^(nd) Ed., pp. 754-757(2002). In addition the liquid dosage forms may include additives, suchas: (a) disintegrating agents; (b) dispersing agents; (c) wettingagents; (d) at least one preservative, (e) viscosity enhancing agents,(f) at least one sweetening agent, and (g) at least one flavoring agent.In some embodiments, the aqueous dispersions can further include acrystalline inhibitor.

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In one embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In another embodiment, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet another embodiment, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still anotherembodiment, no agitation is necessary to maintain a homogeneous aqueousdispersion.

Intranasal Formulations

Intranasal formulations are known in the art and are described in, forexample, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each ofwhich is specifically incorporated by reference. Formulations thatinclude an FXR modulator in combination with or separately from thesecond agent, which are prepared according to these and other techniqueswell-known in the art are prepared as solutions in saline, employingbenzyl alcohol or other suitable preservatives, fluorocarbons, and/orother solubilizing or dispersing agents known in the art. See, forexample, Ansel, H. C. et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, Sixth Ed. (1995). Preferably these compositions andformulations are prepared with suitable nontoxic pharmaceuticallyacceptable ingredients. These ingredients are known to those skilled inthe preparation of nasal dosage forms and some of these can be found inREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 22st edition, 2012, astandard reference in the field. The choice of suitable carriers ishighly dependent upon the exact nature of the nasal dosage form desired,e.g., solutions, suspensions, ointments, or gels. Nasal dosage formsgenerally contain large amounts of water in addition to the activeingredient. Minor amounts of other ingredients such as pH adjusters,emulsifiers or dispersing agents, preservatives, surfactants, gellingagents, or buffering and other stabilizing and solubilizing agents mayalso be present. The nasal dosage form should be isotonic with nasalsecretions.

For administration by inhalation described herein may be in a form as anaerosol, a mist or a powder. Pharmaceutical compositions describedherein are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebulizer, with the use of asuitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the compound described herein and a suitable powder base such aslactose or starch.

Buccal Formulations

Buccal formulations may be administered using a variety of formulationsknown in the art. For example, such formulations include, but are notlimited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and5,739,136, each of which is specifically incorporated by reference. Inaddition, the buccal dosage forms described herein can further include abioerodible (hydrolysable) polymeric carrier that also serves to adherethe dosage form to the buccal mucosa. The buccal dosage form isfabricated so as to erode gradually over a predetermined time period,wherein the delivery is provided essentially throughout. Buccal drugdelivery, as will be appreciated by those skilled in the art, avoids thedisadvantages encountered with oral drug administration, e.g., slowabsorption, degradation of the active agent by fluids present in thegastrointestinal tract and/or first-pass inactivation in the liver. Withregard to the bioerodible (hydrolysable) polymeric carrier, it will beappreciated that virtually any such carrier can be used, so long as thedesired drug release profile is not compromised, and the carrier iscompatible with an FXR modulator and a second agent, and any othercomponents that may be present in the buccal dosage unit. Generally, thepolymeric carrier comprises hydrophilic (water-soluble andwater-swellable) polymers that adhere to the wet surface of the buccalmucosa. Examples of polymeric carriers useful herein include acrylicacid polymers and co, e.g., those known as “carbomers” (Carbopol®, whichmay be obtained from B.F. Goodrich, is one such polymer). Othercomponents may also be incorporated into the buccal dosage formsdescribed herein include, but are not limited to, disintegrants,diluents, binders, lubricants, flavoring, colorants, preservatives, andthe like. For buccal or sublingual administration, the compositions maytake the form of tablets, lozenges, or gels formulated in a conventionalmanner.

Transdermal Formulations

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122,3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636,3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084,4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and6,946,144, each of which is specifically incorporated by reference inits entirety.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In one embodiments, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound ofthe compounds described herein; (2) a penetration enhancer; and (3) anaqueous adjuvant. In addition, transdermal formulations can includeadditional components such as, but not limited to, gelling agents,creams and ointment bases, and the like. In some embodiments, thetransdermal formulation can further include a woven or non-woven backingmaterial to enhance absorption and prevent the removal of thetransdermal formulation from the skin. In other embodiments, thetransdermal formulations described herein can maintain a saturated orsupersaturated state to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds described herein. Therate of absorption can be slowed by using rate-controlling membranes orby trapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

Injectable Formulations

Formulations that include the compounds described herein, suitable forintramuscular, subcutaneous, or intravenous injection may includephysiologically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations may include aqueous or nonaqueous solutions, preferablywith physiologically compatible buffers or excipients. Such excipientsare generally known in the art.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical formulations for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

Other Formulations

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compounds can contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Synthesis of Compounds

In some embodiments, the synthesis of compounds described herein areaccomplished using means described in the chemical literature, using themethods described herein, or by a combination thereof. In addition,solvents, temperatures and other reaction conditions presented hereinmay vary.

In some embodiments, the starting materials and reagents used for thesynthesis of the compounds described herein are synthesized or areobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, FischerScientific (Fischer Chemicals), and AcrosOrganics.

In further embodiments, the compounds described herein, and otherrelated compounds having different substituents are synthesized usingtechniques and materials described herein as well as those that arerecognized in the field, such as described, for example, in Fieser andFieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley andSons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, Advanced OrganicChemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg, Advanced OrganicChemistry 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, Protective Groups in Organic Synthesis 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as disclosed herein maybe derived from reactions and the reactions may be modified by the useof appropriate reagents and conditions, for the introduction of thevarious moieties found in the formulae as provided herein.

In some embodiments, the compounds described herein are prepared asoutlined in the following schemes.

Scheme 1 provides a synthetic procedure generally applicable to thesynthesis of compounds of Formulae (I) and (III) according to proceduresfound here and elsewhere, e.g., PCT/US2015/062017 herein incorporated byreference in its entirety.

Scheme 2 provides a synthetic procedure generally applicable to thesynthesis of compounds of Formulae (II) and (IV) according to proceduresfound here and elsewhere, e.g., PCT/US2015/062017 herein incorporated byreference in its entirety.

The following examples are offered for purposes of illustration, and arenot intended to limit the scope of the claims provided herein. Allliterature citations in these examples and throughout this specificationare incorporated herein by references for all legal purposes to beserved thereby. The starting materials and reagents used for thesynthesis of the compounds described herein may be synthesized or can beobtained from commercial sources, such as, but not limited to,Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

Example 3: Synthesis of (E)-isopropyl6-(3,4-difluorobenzoyl)-4,4-dimethyl-3-(trifluoromethyl)-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(see also PCT/US2015/062017). Generally Applicable to the Synthesis ofCompounds of Formulae (I), (III), and (IIIa)

Step 1: A solution of hydrazine hydrate (34.4 g, 0.687 mol, 1.1 eq) inethanol (400 mL) was added to a solution of compound 1 (150 g, 0.62 mol)in ethanol (1000 mL) at 0° C. The reaction was allowed to warm to roomtemperature and stirred for 24 hr. The reaction was concentrated invacuo, dissolved in ethyl acetate (2000 mL), washed with 5% citric acid(2000 mL), sat′d NaHCO₃ (2000 mL) and brine, dried (MgSO₄), andconcentrated in vacuo to afford a light yellow solid, compound 2 (113 g,88%).

Step 2: To a solution of compound 2 (20.0 g, 96.1 mmol) in acetic acid(200 mL) was added sodium acetate (23.6 g, 288.3 mmol, 3.0 eq.). To thesuspended solution was added Br₂ (14.7 mL, 288.3 mmol, 3.0 eq.)dropwise. The resulting mixture was stirred at room temperature for 10minutes, and then heated at 100° C. in a sealed-tube for 5 hr. Thesolvent and Br₂ was removed in vacuo. The residue was diluted with ethylacetate (600 mL), washed with water (2×600 mL), saturated NaHCO₃ (600mL), and brine. The organic phase was dried over MgSO₄, and concentratedin vacuo. The crude product was purified by column chromatography (SiO₂,DCM/EA=9/1) to afford an ivory solid 3 (20 g×2 batch; 51.4 g, 188.3 mol,98%).

Step 3: A solution of compound 3 (96.5 g, 353.4 mmol, 1.0 eq.) in dryTHF (1.2 L), and was cooled in an ice-water bath. MeMgBr (471 mL, 3M inether solution, 1.41 mol, 4.0 eq.) was added dropwise. The resultingmixture was stirred at 0° C. for 30 minutes, then room temperatureovernight. The reaction was cooled to 0° C., then quenched withsaturated NH₄Cl solution (1.6 L). The organic phase was washed withbrine, and dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by column chromatography (SiO₂, DCM/EA=9/1) toafford an ivory solid 4 (69.1 g, 253.2 mmol, 72%).

Step 4: To a suspension of indium(

) bromide (6.5 g, 18.3 mmol, 0.1 eq.) in dichloromethane (500 mL) wasadded trimethylsilyl cyanide (69 mL, 549.4 mmol, 3.0 eq.). To thismixture, at room temperature, was added dropwise compound 4 (50.0 g,183.1 mmol, 1.0 eq.) in dichloromethane (1500 mL). The resulting mixturewas stirred at room temperature overnight. Saturated NaHCO₃was added andthe mixture was filtered through a celite pad. The filtrate waspartitioned between saturated NaHCO₃and dichloromethane and the aqueouslayer was extracted one more time with ethyl acetate. The combinedorganic layers were dried over MgSO₄, filtered and concentrated. Thecrude product was purified by column chromatography (SiO₂, DCM toDCM/MeOH=30/1) to afford a brown oil 5 (50 g×2 batch; 107.1 g).

Step 5: To a solution of compound 5 (56.3 g, 199.7 mmol, 1.0 eq.) inCH₃CN (1600 mL), was added K₂CO₃ (82.8 g, 599.1 mmol, 3.0 eq.) and PMBCl(32.5 mL, 239.6 mmol, 1.2 eq.). The mixture was heated at reflux for 2hr. The reaction was cooled to room temperature. The inorganic solid wasremoved by filtration, and the mother liquid was concentrated in vacuo.The crude product was purified by column chromatography (SiO₂,Hex/EA=9/1) to afford a yellow oil 6 (56.3 g, 50.8 g×2 batch, 133.5 g,332.0 mmol, 91%).

Step 6A: To a suspension of zinc dust (4.1 g, 31.0 mmol, 2.0 eq.) in dryether (40 mL) was added dropwise HCl (2M solution in ether; 2 mL, 0.13eq.). The suspension was heated to reflux, and isopropyl bromoacetate (4mL, 31.0 mmol, 2.5 eq.) was added dropwise. The solution was stirred atthis temperature for 4 hr and cooled to room temperature.

Step 6B: To a solution of 6 ((5.0 g, 12.4 mmol, 1.0 eq.) in anhydrousTHF (100 mL) was added Pd(P(tBu)₃)₂ (5.1 g, 9.94 mmol, 0.8 eq.) underargon. The solution of (2-isopropoxy-2-oxoethyl) zinc bromide from step6A was added drop-wise. The resulting mixture was stirred in an oil bathwith heating from room temperature to 75° C. within 10 minutes. Thereaction mixture was heated at 75° C. for 2 hr. The reaction mixture wascooled to room temperature and quenched with saturated NH₄Cl (200 mL).After extraction of the product with ethyl acetate, the crude productwas purified by column chromatography (SiO₂, Hex/EA=9/1→Hex/EA=6/1) toafford an ivory oil 7 (2.4 g, 5.7 mmol, 46%).

Step 7: To a solution of compound 7 (7.8 g, 18.42 mmol, 1.0 eq) in THF(80 mL) and iPrOH (160 mL) was added Boc anhydride (8.04 g, 36.84 mmol,2.0 eq) and a Ra—Ni slurry in water (40 mL). The resulting mixture washydrogenated at H₂ 40 psi for 4 h. The catalyst was carefully removed byfiltration. The filtrate was concentrated in vacuo. The crude productwas purified by column chromatography (SiO₂, HX/EA=5/1) to afford asticky oil 8 (6.9 g, 71%).

Step 8: Compound 8 (6.9 g, 13.08 mmol) was dissolved in Bredereck'sreagent (55 mL). The solution was flushed with nitrogen, and then heatedat 115° C. in a sealed tube for 3 h. The mixture was diluted with CH₂Cl₂(500 mL). The organic phase was washed with water and brine, dried overMgSO₄, filtered and concentrated. The crude mixture was purified bycolumn chromatography (SiO₂, Hx/EA=2/1) to afford a sticky oil 9 (6.8 g,89%).

Step 9A: To a solution of compound 9 (6.8 g, 11.67 mmol) in dry CH₂Cl₂(50 mL) was added TFA (30 mL). The solution was stirred at roomtemperature for 15 minutes. The solvent was removed in vacuo. Theresidue was diluted with CH₂Cl₂ (500 mL), washed with saturatedNaHCO₃and brine, dried over MgSO₄, filtered and concentrated to affordthe free amine intermediate.

Step 9B: To a solution of the intermediate from step 9A in iPrOH (100mL) was added concentrated HCl in water (3.4 mL). The resulting mixturewas heated at 100° C. in a sealed tube for 18 h. The solvent was removedin vacuo. The residue was dissolved in CH₂Cl₂ (500 mL), washed withsaturated NaHCO₃and brine, dried over MgSO₄, filtered and concentrated.The crude product was purified by column chromatography (SiO₂,Hx/EA=2/1) to afford solid 10 (3.7 g, 72%).

Step 10: To a solution of 10 (2 g, 4.57 mmol) in dry THF (50 mL) wasadded LiHMDS (1M in hexane, 6.85 mL, 1.5 eq) dropwise at 0° C.3,4-difluorobenzoyl chloride (1.15 mL, 2.0 eq) was then added dropwise.The resulting mixture was stirred at room temperature for 2 h. Themixture was quenched with saturated NH₄Cl and extracted with ethylacetate. The organic solution was dried over MgSO₄, filtered andconcentrated. The crude product was purified by column chromatography(SiO₂, Hx/EA=5/1) to afford solid 11 (2 g, 75%).

Step 11: A solution of compound 11 (2 g, 3.46 mmol) in TFA (20 mL) washeated at 90° C. in a sealed tube for 10 minutes. The TFA was removed invacuo and the crude product was purified by column chromatography (SiO₂,DCM/Hx/EA=10/20/0.5) to afford the title compound 12 (1.3 g, 82%). LCMSm/z: 444.1 [M+H]+.

Example 4: Synthesis of (E)-ethyl6-(3,4-difluorobenzoyl)-3,4,4-trimethyl-1,4,5,6-tetrahydropyrazolo[3,4-d]azepine-8-carboxylate(23) (see also PCT/US2015/062017). Generally Applicable to the Synthesisof Compounds of Formulae (I), (III), and (IIIa)

In some embodiments, the compounds described herein are prepared asoutlined in the following schemes:

Scheme 3 as applicable to compounds of the Formulae (VII),(VIIa)-(VIIj), (VIII), (VIIIa)-(VIIIj), see also PCT/IB2015/002549herein incorporated by reference in its entirety, Published as WO2016/103037:

Scheme 4 as applicable to compounds of the Formulae (VII),(VIIa)-(VIIj), (VIII), (VIIIa)-(VIIIj), see also PCT/IB2015/002549herein incorporated by reference in its entirety, Published as WO2016/103037

Example 5: Synthesis of propan-2-yl4-chloro-12-(3,4-dichlorobenzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(31) See Also PCT/IB2015/002549 Herein Incorporated by Reference in itsEntirety, Published as WO 2016/103037

Example 6: Synthesis of propan-2-yl4-chloro-12-(3,4-difluorobenzoyl)-14,14-dimethyl-6,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(33)

To a stirred solution of compound 31 (52 mg, 0.15 mmol) and DIPEA (0.13mL, 0.75 mmol) in dichloromethane (4 mL), 3,4-difluorobenzoyl chloride(0.09 mL, 0.75 mmol) in DCM (1 mL) was added. The reaction mixture wasstirred at rt for 10 mins and it was then diluted with DCM. The mixturewas washed with aqueous NaHCO₃and brine. The organics were dried overanhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by silica gel column chromatography (PE/EA, from 20/1 to 10/1)to afford the title compound (33 mg, 43%). LC-MS: 474.30 (M+H),C₂₄H₂₂C₁F₂N₃O₃. ¹H NMR (CDCl₃, 400 MHz) δ 11.10 (br, 1H), 8.23 (s, 1H),8.04 (s, 1H), 7.90 (s, 1H), 7.54-7.49 (m, 1H), 7.38-7.34 (m, 1H),7.29-7.22 (m, 1H), 5.19-5.13 (m, 1H), 4.06 (br, 1H), 1.56 (s, 6H), 1.22(d, J=6.4 Hz, 6H).

Example 7: Synthesis of propan-2-yl5-chloro-12-(3,4-difluorobenzoyl)-14,14-dimethyl-3,8,12-triazatricyclo[7.5.0.02,7]tetradeca-1(9),2,4,6,10-pentaene-10-carboxylate(44) See Also PCT/IB2015/002549 Herein Incorporated by Reference in itsEntirety, Published as WO 2016/103037

Synthesis of3-chloro-8-(3,4-difluorobenzoyl)-N-isopropyl-10,10-dimethyl-5,8,9,10-tetrahydropyrido[2′,3′:4,5]pyrrolo[2,3-d]azepine-6-carboxamide(85). General Procedure Applicable to Compounds of the Formulae (VII),(VIId), (VIII), and (VIIId)

To a solution of isopropyl amine (70 mg, 1.10 mol) in toluene, trimethylaluminium [0.4 mL (2 M solution in toluene), 0.90 mol] was added at 0°C. After 15 minutes, compound 44 (110 mg, 0.23 mol) was added andreaction mixture was heated at 110° C. in a seal tube for 16 h. Thereaction was quenched with ice water and extracted with ethyl acetate.The combined ethyl acetate layers were washed with water and brine,dried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified on silica gel using 30% ethyl acetate in hexane toafford compound 85 (40 mg, 51%) as a yellow solid. LC-MS: 473.1.

Scheme 5 is generally applicable to compounds of Formula (XI)

Scheme 6 is generally applicable to compounds of Formula (XII)

Example 8: Phase 1 Study to Evaluate Safety of a Combination of an FXRModulator and a DPP-IV Inhibitor in Subjects with Non-AlcoholicSteatohepatitis (NASH) and Advanced Fibrosis

The primary objective of this study is to characterize the safety,tolerability and dose-limiting toxicities (DLTs) for a combination of anFXR modulator and a DPP-IV inhibitor when administered orally tosubjects with biopsy-proven NASH with advanced liver fibrosis.

-   -   The safety and tolerability of multiple doses of an FXR        modulator and a DPP-IV inhibitor;    -   The effects of multiple doses of a combination of an FXR        modulator and a DPP-IV inhibitor on insulin resistance and        glucose homeostasis; and    -   Effects of a combination of an FXR modulator and a DPP-IV        inhibitor on hepatocellular function as measured by assessment        of liver enzymes and biochemical markers of hepatic and        metabolic function and inflammation.

Patients: Eligible subjects will be men and women 18 years to 75 yearsof age.

Criteria:

Inclusion Criteria:

-   -   Institutional Review Board (IRB approved written Informed        Consent and privacy language as per national regulation (eg,        Health Insurance Portability and Accountability Act [HIPAA]        Authorization for US sites) must be obtained from the subject or        legally authorized representative prior to any study related        procedures, including screening evaluations and tests    -   Subject is ≥18 years of age and <76 years old at the time of        consent    -   Subject has had a percutaneous liver biopsy within 12 months        from Screening that shows a definitive diagnosis of NASH with        advanced (Brunt stage 3) hepatic fibrosis

Exclusion Criteria:

-   -   Subject is a pregnant or lactating female    -   Subject with current, significant alcohol consumption or a        history of significant alcohol consumption for a period of more        than 3 consecutive months any time within 1 year prior to        screening. Significant alcohol consumption is defined as more        than 20 gram per day in females and more than 30 grams per day        in males, on average (a standard drink in the US is considered        to be 14 grams of alcohol).    -   Subject is unable to reliably quantify alcohol consumption based        upon local study physician judgment.    -   Subject uses drugs historically associated with nonalcoholic        fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic        glucocorticoids, tetracyclines, tamoxifen, estrogens at doses        greater than those used for hormone replacement, anabolic        steroids, valproic acid, and other known hepatotoxins) for more        than 2 weeks in the year prior to Screening.    -   Subject requires use of drugs with a narrow therapeutic window        metabolized by CYP3A4 such as fast acting opioids (alfentanil        and fentanyl), immunosuppressive drugs (cyclosporine, sirolimus,        and tacrolimus), some cardiovascular agents (ergotamine,        quinidine and dihydroergotamine), and select psychotropic agents        (pimozide).    -   Subject has prior or has planned (during the study period)        bariatric surgery (eg, gastroplasty, Roux-en-Y gastric bypass).    -   Subject has concurrent infection including diagnoses of fever of        unknown origin and evidence of possible central line sepsis        (subjects must be afebrile at the start of therapy).    -   Subject with a platelet count below 100,000/mm3 at Screening.    -   Subject with clinical evidence of hepatic decompensation as        defined by the presence of any of the following abnormalities at        Screening:    -   Serum albumin less than 3.5 grams/deciliter (g/dL).    -   An INR greater than 1.1.    -   Direct bilirubin greater than 1.3 milligrams per deciliter        (mg/dL).    -   Subject has a history of bleeding esophageal varices, ascites or        hepatic encephalopathy    -   Subject has a history of hepatitis C. Patients found on        screening to have hepatitis C antibody, even if PCR negative for        HCV RNA, are excluded from this study.    -   Subject has evidence of other forms of chronic liver disease:    -   Hepatitis B as defined by presence of hepatitis B surface        antigen.    -   Evidence of ongoing autoimmune liver disease as defined by        compatible liver histology.    -   Primary biliary cirrhosis as defined by the presence of at least        2 of these criteria (i) Biochemical evidence of cholestasis        based mainly on alkaline phosphatase elevation (ii) Presence of        anti-mitochondrial antibody (iii) Histologic evidence of        nonsuppurative destructive cholangitis and destruction of        interlobular bile ducts.    -   Primary sclerosing cholangitis.    -   Wilson's disease as defined by ceruloplasmin below the limits of        normal and compatible liver histology.    -   Alpha-1-antitrypsin deficiency as defined by diagnostic features        in liver histology (confirmed by alpha-1 antitrypsin level less        than normal; exclusion at the discretion of the study        physician).    -   History of hemochromatosis or iron overload as defined by        presence of 3+ or 4+ stainable iron on liver biopsy.    -   Drug-induced liver disease as defined on the basis of typical        exposure and history.    -   Known bile duct obstruction.    -   Suspected or proven liver cancer.    -   Any other type of liver disease other than NASH.    -   Subject with serum ALT greater than 300 units per liter (U/L) at        Screening.    -   Subject with serum creatinine of 1.5 mg/dL or greater at        Screening.    -   Subject using of any prescription or over-the-counter medication        or herbal remedy that are believed to improve or treat NASH or        liver disease or obesity during the period beginning 30 days        prior to randomization. Subjects who are using Vitamin E or        omega-3 fatty acids may continue their use.    -   Subject had major surgery within 8 weeks prior to Day 0,        significant traumatic injury, or anticipation of need for major        surgical procedure during the course of the study.    -   Subject with a history of biliary diversion.    -   Subject with known positivity for Human Immunodeficiency Virus        infection.    -   Subject with an active, serious medical disease with likely life        expectancy of less than 5 years.    -   Subject with active substance abuse, including inhaled or        injection drugs, in the year prior to Screening.    -   Subject who has clinically significant and uncontrolled        cardiovascular disease (eg, uncontrolled hypertension,        myocardial infarction, unstable angina), New York Heart        Association Grade II or greater congestive heart failure,        serious cardiac arrhythmia requiring medication, or Grade II or        greater peripheral vascular disease within 12 months prior to        Day 0.    -   Subject has participated in an investigational new drug (IND)        trial in the 30 days before randomization.    -   Subject has a clinically significant medical or psychiatric        condition considered a high risk for participation in an        investigational study.    -   Subject has any other condition which, in the opinion of the        Investigator, would impede compliance or hinder completion of        the study.    -   Subject has been previously exposed to GR MD 02.    -   Subject with known allergies to the study drug or any of its        excipients.    -   Subject with malignant disease (other than basal and squamous        cell carcinoma of the skin and in situ carcinoma of the cervix)        with at least 5 years of follow-up showing no recurrence.    -   Subject has an abnormal chest x-ray indicative of acute or        chronic lung disease on screening examination.

Study Design:

-   -   Allocation: Randomized    -   Endpoint Classification: Safety/Efficacy Study    -   Intervention Model: Parallel Assignment    -   Masking: Double Blind (Subject, Investigator)    -   Primary Purpose: Treatment

Primary Outcome Measures:

-   -   The primary objective of this study is to characterize the        safety, which includes the tolerability and dose-limiting        toxicity (DLT), for a combination of an FXR modulator and a        DPP-IV inhibitor when administered to subjects with        biopsy-proven NASH with advanced liver fibrosis. Specifically,        this measure will be assessed by number of subjects experiencing        treatment emergent adverse events indicative of DLT.

Secondary Outcome Measures:

-   -   A secondary objective is to evaluate change in serum alanine        aminotransferase (ALT), aspartate aminotransferase (AST), ratio        of AST:ALT, alkaline phosphatase, and gamma glutamyl        transpeptidase (GGTP); change in AST/platelet ratio index. [Time        Frame: Baseline; Week 7 (End of Study)] [Designated as safety        issue: No]    -   A secondary objective for this study is to evaluate change in        serum alanine aminotransferase (ALT), aspartate aminotransferase        (AST), ratio of AST:ALT, alkaline phosphatase, and gamma        glutamyl transpeptidase (GGTP) levels; and change in        AST/platelet ratio index.    -   A secondary objective for this study is to evaluate changes in        exploratory pharmacodynamic biomarkers in serum [Time Frame:        Baseline; Week 7 (End of Study)] [Designated as safety issue:        No]    -   A secondary objective for this study is to evaluate levels of        exploratory pharmacodynamic biomarkers in serum including        galectin-3, inflammatory, cell-death, and fibrosis markers.    -   Hepatocellular function as measured by assessment of liver        enzymes and biochemical markers of hepatic and metabolic        function.

Arms Assigned Interventions Active Comparator: Cohort 1 Drug: Compound1, Compound 2, Patient receives dose of or Compound 3 Compound 1,Compound 2, or Drug: Placebo Compound 3 or Placebo Active Comparator:Cohort 2 Drug: Compound 1, Compound 2, Patient receives dose of orCompound 3 Compound 1, Compound 2, or Drug: Placebo Compound 3 orPlacebo Active Comparator: Cohort 3 Drug: Compound 1, Compound 2,Patient receives dose of or Compound 3 Compound 1, Compound 2, or Drug:Placebo Compound 3 or Placebo

This study is a dose ranging study to assess in sequential fashion, thesafety, tolerability, and dose limiting toxicities (DLTs) of acombination of an FXR modulator and a DPP-IV inhibitor in subjects withbiopsy-proven NASH with advanced fibrosis.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

Example 9: Phase 1 Study to Evaluate Safety of a Combination of an FXRModulator and an SGL2 Inhibitor in Subjects with Non-AlcoholicSteatohepatitis (NASH) and Advanced Fibrosis

The primary objective of this study is to characterize the safety,tolerability and dose-limiting toxicities (DLTs) for a combination of anFXR modulator and an SGLT2 inhibitor when administered orally tosubjects with biopsy-proven NASH with advanced liver fibrosis.

-   -   The safety and tolerability of multiple doses of an FXR        modulator and an SGLT2 inhibitor;    -   The effects of multiple doses of a combination of an FXR        modulator and an SGLT2 inhibitor on insulin resistance and        glucose homeostasis; and    -   Effects of a combination of an FXR modulator and an SGLT2        inhibitor on hepatocellular function as measured by assessment        of liver enzymes and biochemical markers of hepatic and        metabolic function and inflammation.

Patients: Eligible subjects will be men and women 18 years to 75 yearsof age.

Criteria:

Inclusion Criteria:

-   -   Institutional Review Board (IRB approved written Informed        Consent and privacy language as per national regulation (eg,        Health Insurance Portability and Accountability Act [HIPAA]        Authorization for US sites) must be obtained from the subject or        legally authorized representative prior to any study related        procedures, including screening evaluations and tests    -   Subject is ≥18 years of age and <76 years old at the time of        consent    -   Subject has had a percutaneous liver biopsy within 12 months        from Screening that shows a definitive diagnosis of NASH with        advanced (Brunt stage 3) hepatic fibrosis

Exclusion Criteria:

-   -   Subject is a pregnant or lactating female    -   Subject with current, significant alcohol consumption or a        history of significant alcohol consumption for a period of more        than 3 consecutive months any time within 1 year prior to        screening. Significant alcohol consumption is defined as more        than 20 gram per day in females and more than 30 grams per day        in males, on average (a standard drink in the US is considered        to be 14 grams of alcohol).    -   Subject is unable to reliably quantify alcohol consumption based        upon local study physician judgment.    -   Subject uses drugs historically associated with nonalcoholic        fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic        glucocorticoids, tetracyclines, tamoxifen, estrogens at doses        greater than those used for hormone replacement, anabolic        steroids, valproic acid, and other known hepatotoxins) for more        than 2 weeks in the year prior to Screening.    -   Subject requires use of drugs with a narrow therapeutic window        metabolized by CYP3A4 such as fast acting opioids (alfentanil        and fentanyl), immunosuppressive drugs (cyclosporine, sirolimus,        and tacrolimus), some cardiovascular agents (ergotamine,        quinidine and dihydroergotamine), and select psychotropic agents        (pimozide).    -   Subject has prior or has planned (during the study period)        bariatric surgery (eg, gastroplasty, Roux-en-Y gastric bypass).    -   Subject has concurrent infection including diagnoses of fever of        unknown origin and evidence of possible central line sepsis        (subjects must be afebrile at the start of therapy).    -   Subject with a platelet count below 100,000/mm3 at Screening.    -   Subject with clinical evidence of hepatic decompensation as        defined by the presence of any of the following abnormalities at        Screening:    -   Serum albumin less than 3.5 grams/deciliter (g/dL).    -   An INR greater than 1.1.    -   Direct bilirubin greater than 1.3 milligrams per deciliter        (mg/dL).    -   Subject has a history of bleeding esophageal varices, ascites or        hepatic encephalopathy    -   Subject has a history of hepatitis C. Patients found on        screening to have hepatitis C antibody, even if PCR negative for        HCV RNA, are excluded from this study.    -   Subject has evidence of other forms of chronic liver disease:    -   Hepatitis B as defined by presence of hepatitis B surface        antigen.    -   Evidence of ongoing autoimmune liver disease as defined by        compatible liver histology.    -   Primary biliary cirrhosis as defined by the presence of at least        2 of these criteria (i) Biochemical evidence of cholestasis        based mainly on alkaline phosphatase elevation (ii) Presence of        anti-mitochondrial antibody (iii) Histologic evidence of        nonsuppurative destructive cholangitis and destruction of        interlobular bile ducts.    -   Primary sclerosing cholangitis.    -   Wilson's disease as defined by ceruloplasmin below the limits of        normal and compatible liver histology.    -   Alpha-1-antitrypsin deficiency as defined by diagnostic features        in liver histology (confirmed by alpha-1 antitrypsin level less        than normal; exclusion at the discretion of the study        physician).    -   History of hemochromatosis or iron overload as defined by        presence of 3+ or 4+ stainable iron on liver biopsy.    -   Drug-induced liver disease as defined on the basis of typical        exposure and history.    -   Known bile duct obstruction.    -   Suspected or proven liver cancer.    -   Any other type of liver disease other than NASH.    -   Subject with serum ALT greater than 300 units per liter (U/L) at        Screening.    -   Subject with serum creatinine of 1.5 mg/dL or greater at        Screening.    -   Subject using of any prescription or over-the-counter medication        or herbal remedy that are believed to improve or treat NASH or        liver disease or obesity during the period beginning 30 days        prior to randomization. Subjects who are using Vitamin E or        omega-3 fatty acids may continue their use.    -   Subject had major surgery within 8 weeks prior to Day 0,        significant traumatic injury, or anticipation of need for major        surgical procedure during the course of the study.    -   Subject with a history of biliary diversion.    -   Subject with known positivity for Human Immunodeficiency Virus        infection.    -   Subject with an active, serious medical disease with likely life        expectancy of less than 5 years.    -   Subject with active substance abuse, including inhaled or        injection drugs, in the year prior to Screening.    -   Subject who has clinically significant and uncontrolled        cardiovascular disease (eg, uncontrolled hypertension,        myocardial infarction, unstable angina), New York Heart        Association Grade II or greater congestive heart failure,        serious cardiac arrhythmia requiring medication, or Grade II or        greater peripheral vascular disease within 12 months prior to        Day 0.    -   Subject has participated in an investigational new drug (IND)        trial in the 30 days before randomization.    -   Subject has a clinically significant medical or psychiatric        condition considered a high risk for participation in an        investigational study.    -   Subject has any other condition which, in the opinion of the        Investigator, would impede compliance or hinder completion of        the study.    -   Subject has been previously exposed to GR MD 02.    -   Subject with known allergies to the study drug or any of its        excipients.    -   Subject with malignant disease (other than basal and squamous        cell carcinoma of the skin and in situ carcinoma of the cervix)        with at least 5 years of follow-up showing no recurrence.    -   Subject has an abnormal chest x-ray indicative of acute or        chronic lung disease on screening examination.

Study Design:

-   -   Allocation: Randomized    -   Endpoint Classification: Safety/Efficacy Study    -   Intervention Model: Parallel Assignment    -   Masking: Double Blind (Subject, Investigator)    -   Primary Purpose: Treatment

Primary Outcome Measures:

-   -   The primary objective of this study is to characterize the        safety, which includes the tolerability and dose-limiting        toxicity (DLT), for a combination of an FXR modulator and an        SGLT2 inhibitor when administered to subjects with biopsy-proven        NASH with advanced liver fibrosis. Specifically, this measure        will be assessed by number of subjects experiencing treatment        emergent adverse events indicative of DLT.

Secondary Outcome Measures:

-   -   A secondary objective is to evaluate change in serum alanine        aminotransferase (ALT), aspartate aminotransferase (AST), ratio        of AST:ALT, alkaline phosphatase, and gamma glutamyl        transpeptidase (GGTP); change in AST/platelet ratio index. [Time        Frame: Baseline; Week 7 (End of Study)] [Designated as safety        issue: No]    -   A secondary objective for this study is to evaluate change in        serum alanine aminotransferase (ALT), aspartate aminotransferase        (AST), ratio of AST:ALT, alkaline phosphatase, and gamma        glutamyl transpeptidase (GGTP) levels; and change in        AST/platelet ratio index.    -   A secondary objective for this study is to evaluate changes in        exploratory pharmacodynamic biomarkers in serum [Time Frame:        Baseline; Week 7 (End of Study)] [Designated as safety issue:        No]    -   A secondary objective for this study is to evaluate levels of        exploratory pharmacodynamic biomarkers in serum including        galectin-3, inflammatory, cell-death, and fibrosis markers.    -   Hepatocellular function as measured by assessment of liver        enzymes and biochemical markers of hepatic and metabolic        function.

This study is a dose ranging study to assess in sequential fashion, thesafety, tolerability, and dose limiting toxicities (DLTs) of acombination of an FXR modulator and an SGLT2 inhibitor in subjects withbiopsy-proven NASH with advanced fibrosis.

Example 10: Phase 1 Study to Evaluate Safety of a Combination of an FXRModulator and an ASK1 Inhibitor in Subjects with Non-AlcoholicSteatohepatitis (NASH) and Advanced Fibrosis

The primary objective of this study is to characterize the safety,tolerability and dose-limiting toxicities (DLTs) for a combination of anFXR modulator and an ASK1 inhibitor when administered orally to subjectswith biopsy-proven NASH with advanced liver fibrosis.

-   -   The safety and tolerability of multiple doses of an FXR        modulator and an ASK1 inhibitor;    -   The effects of multiple doses of a combination of an FXR        modulator and an ASK1 inhibitor on insulin resistance and        glucose homeostasis; and    -   Effects of a combination of an FXR modulator and an ASK1        inhibitor on hepatocellular function as measured by assessment        of liver enzymes and biochemical markers of hepatic and        metabolic function and inflammation.

Patients: Eligible subjects will be men and women 18 years to 75 yearsof age.

Criteria:

Inclusion Criteria:

-   -   Institutional Review Board (IRB approved written Informed        Consent and privacy language as per national regulation (eg,        Health Insurance Portability and Accountability Act [HIPAA]        Authorization for US sites) must be obtained from the subject or        legally authorized representative prior to any study related        procedures, including screening evaluations and tests    -   Subject is ≥18 years of age and <76 years old at the time of        consent    -   Subject has had a percutaneous liver biopsy within 12 months        from Screening that shows a definitive diagnosis of NASH with        advanced (Brunt stage 3) hepatic fibrosis

Exclusion Criteria:

-   -   Subject is a pregnant or lactating female    -   Subject with current, significant alcohol consumption or a        history of significant alcohol consumption for a period of more        than 3 consecutive months any time within 1 year prior to        screening. Significant alcohol consumption is defined as more        than 20 gram per day in females and more than 30 grams per day        in males, on average (a standard drink in the US is considered        to be 14 grams of alcohol).    -   Subject is unable to reliably quantify alcohol consumption based        upon local study physician judgment.    -   Subject uses drugs historically associated with nonalcoholic        fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic        glucocorticoids, tetracyclines, tamoxifen, estrogens at doses        greater than those used for hormone replacement, anabolic        steroids, valproic acid, and other known hepatotoxins) for more        than 2 weeks in the year prior to Screening.    -   Subject requires use of drugs with a narrow therapeutic window        metabolized by CYP3A4 such as fast acting opioids (alfentanil        and fentanyl), immunosuppressive drugs (cyclosporine, sirolimus,        and tacrolimus), some cardiovascular agents (ergotamine,        quinidine and dihydroergotamine), and select psychotropic agents        (pimozide).    -   Subject has prior or has planned (during the study period)        bariatric surgery (eg, gastroplasty, Roux-en-Y gastric bypass).    -   Subject has concurrent infection including diagnoses of fever of        unknown origin and evidence of possible central line sepsis        (subjects must be afebrile at the start of therapy).    -   Subject with a platelet count below 100,000/mm3 at Screening.    -   Subject with clinical evidence of hepatic decompensation as        defined by the presence of any of the following abnormalities at        Screening:    -   Serum albumin less than 3.5 grams/deciliter (g/dL).    -   An INR greater than 1.1.    -   Direct bilirubin greater than 1.3 milligrams per deciliter        (mg/dL).    -   Subject has a history of bleeding esophageal varices, ascites or        hepatic encephalopathy    -   Subject has a history of hepatitis C. Patients found on        screening to have hepatitis C antibody, even if PCR negative for        HCV RNA, are excluded from this study.    -   Subject has evidence of other forms of chronic liver disease:    -   Hepatitis B as defined by presence of hepatitis B surface        antigen.    -   Evidence of ongoing autoimmune liver disease as defined by        compatible liver histology.    -   Primary biliary cirrhosis as defined by the presence of at least        2 of these criteria (i) Biochemical evidence of cholestasis        based mainly on alkaline phosphatase elevation (ii) Presence of        anti-mitochondrial antibody (iii) Histologic evidence of        nonsuppurative destructive cholangitis and destruction of        interlobular bile ducts.    -   Primary sclerosing cholangitis.    -   Wilson's disease as defined by ceruloplasmin below the limits of        normal and compatible liver histology.    -   Alpha-1-antitrypsin deficiency as defined by diagnostic features        in liver histology (confirmed by alpha-1 antitrypsin level less        than normal; exclusion at the discretion of the study        physician).    -   History of hemochromatosis or iron overload as defined by        presence of 3+ or 4+ stainable iron on liver biopsy.    -   Drug-induced liver disease as defined on the basis of typical        exposure and history.    -   Known bile duct obstruction.    -   Suspected or proven liver cancer.    -   Any other type of liver disease other than NASH.    -   Subject with serum ALT greater than 300 units per liter (U/L) at        Screening.    -   Subject with serum creatinine of 1.5 mg/dL or greater at        Screening.    -   Subject using of any prescription or over-the-counter medication        or herbal remedy that are believed to improve or treat NASH or        liver disease or obesity during the period beginning 30 days        prior to randomization. Subjects who are using Vitamin E or        omega-3 fatty acids may continue their use.    -   Subject had major surgery within 8 weeks prior to Day 0,        significant traumatic injury, or anticipation of need for major        surgical procedure during the course of the study.    -   Subject with a history of biliary diversion.    -   Subject with known positivity for Human Immunodeficiency Virus        infection.    -   Subject with an active, serious medical disease with likely life        expectancy of less than 5 years.    -   Subject with active substance abuse, including inhaled or        injection drugs, in the year prior to Screening.    -   Subject who has clinically significant and uncontrolled        cardiovascular disease (eg, uncontrolled hypertension,        myocardial infarction, unstable angina), New York Heart        Association Grade II or greater congestive heart failure,        serious cardiac arrhythmia requiring medication, or Grade II or        greater peripheral vascular disease within 12 months prior to        Day 0.    -   Subject has participated in an investigational new drug (IND)        trial in the 30 days before randomization.    -   Subject has a clinically significant medical or psychiatric        condition considered a high risk for participation in an        investigational study.    -   Subject has any other condition which, in the opinion of the        Investigator, would impede compliance or hinder completion of        the study.    -   Subject has been previously exposed to GR MD 02.    -   Subject with known allergies to the study drug or any of its        excipients.    -   Subject with malignant disease (other than basal and squamous        cell carcinoma of the skin and in situ carcinoma of the cervix)        with at least 5 years of follow-up showing no recurrence.    -   Subject has an abnormal chest x-ray indicative of acute or        chronic lung disease on screening examination.

Study Design:

-   -   Allocation: Randomized    -   Endpoint Classification: Safety/Efficacy Study    -   Intervention Model: Parallel Assignment    -   Masking: Double Blind (Subject, Investigator)    -   Primary Purpose: Treatment

Primary Outcome Measures:

-   -   The primary objective of this study is to characterize the        safety, which includes the tolerability and dose-limiting        toxicity (DLT), for a combination of an FXR modulator and an        ASK1 inhibitor when administered to subjects with biopsy-proven        NASH with advanced liver fibrosis. Specifically, this measure        will be assessed by number of subjects experiencing treatment        emergent adverse events indicative of DLT.

Secondary Outcome Measures:

-   -   A secondary objective is to evaluate change in serum alanine        aminotransferase (ALT), aspartate aminotransferase (AST), ratio        of AST:ALT, alkaline phosphatase, and gamma glutamyl        transpeptidase (GGTP); change in AST/platelet ratio index. [Time        Frame: Baseline; Week 7 (End of Study)] [Designated as safety        issue: No]    -   A secondary objective for this study is to evaluate change in        serum alanine aminotransferase (ALT), aspartate aminotransferase        (AST), ratio of AST:ALT, alkaline phosphatase, and gamma        glutamyl transpeptidase (GGTP) levels; and change in        AST/platelet ratio index.    -   A secondary objective for this study is to evaluate changes in        exploratory pharmacodynamic biomarkers in serum [Time Frame:        Baseline; Week 7 (End of Study)] [Designated as safety issue:        No]    -   A secondary objective for this study is to evaluate levels of        exploratory pharmacodynamic biomarkers in serum including        galectin-3, inflammatory, cell-death, and fibrosis markers.    -   Hepatocellular function as measured by assessment of liver        enzymes and biochemical markers of hepatic and metabolic        function.

This study is a dose ranging study to assess in sequential fashion, thesafety, tolerability, and dose limiting toxicities (DLTs) of acombination of an FXR modulator and an ASK1 inhibitor in subjects withbiopsy-proven NASH with advanced fibrosis.

Example 11: Phase 1 Study to Evaluate Safety of a Combination of an FXRModulator and an GLP-1 Agonist in Subjects with Non-AlcoholicSteatohepatitis (NASH) and Advanced Fibrosis

The primary objective of this study is to characterize the safety,tolerability and dose-limiting toxicities (DLTs) for a combination of anFXR modulator and a GLP-1 agonist when administered orally to subjectswith biopsy-proven NASH with advanced liver fibrosis.

-   -   The safety and tolerability of multiple doses of an FXR        modulator and a GLP-1 agonist;    -   The effects of multiple doses of a combination of an FXR        modulator and a GLP-1 agonist on insulin resistance and glucose        homeostasis; and    -   Effects of a combination of an FXR modulator and a GLP-1 agonist        on hepatocellular function as measured by assessment of liver        enzymes and biochemical markers of hepatic and metabolic        function and inflammation.

Patients: Eligible subjects will be men and women 18 years to 75 yearsof age.

Criteria:

Inclusion Criteria:

-   -   Institutional Review Board (IRB approved written Informed        Consent and privacy language as per national regulation (eg,        Health Insurance Portability and Accountability Act [HIPAA]        Authorization for US sites) must be obtained from the subject or        legally authorized representative prior to any study related        procedures, including screening evaluations and tests    -   Subject is ≥18 years of age and <76 years old at the time of        consent    -   Subject has had a percutaneous liver biopsy within 12 months        from Screening that shows a definitive diagnosis of NASH with        advanced (Brunt stage 3) hepatic fibrosis

Exclusion Criteria:

-   -   Subject is a pregnant or lactating female    -   Subject with current, significant alcohol consumption or a        history of significant alcohol consumption for a period of more        than 3 consecutive months any time within 1 year prior to        screening. Significant alcohol consumption is defined as more        than 20 gram per day in females and more than 30 grams per day        in males, on average (a standard drink in the US is considered        to be 14 grams of alcohol).    -   Subject is unable to reliably quantify alcohol consumption based        upon local study physician judgment.    -   Subject uses drugs historically associated with nonalcoholic        fatty liver disease (NAFLD) (amiodarone, methotrexate, systemic        glucocorticoids, tetracyclines, tamoxifen, estrogens at doses        greater than those used for hormone replacement, anabolic        steroids, valproic acid, and other known hepatotoxins) for more        than 2 weeks in the year prior to Screening.    -   Subject requires use of drugs with a narrow therapeutic window        metabolized by CYP3A4 such as fast acting opioids (alfentanil        and fentanyl), immunosuppressive drugs (cyclosporine, sirolimus,        and tacrolimus), some cardiovascular agents (ergotamine,        quinidine and dihydroergotamine), and select psychotropic agents        (pimozide).    -   Subject has prior or has planned (during the study period)        bariatric surgery (eg, gastroplasty, Roux-en-Y gastric bypass).    -   Subject has concurrent infection including diagnoses of fever of        unknown origin and evidence of possible central line sepsis        (subjects must be afebrile at the start of therapy).    -   Subject with a platelet count below 100,000/mm3 at Screening.    -   Subject with clinical evidence of hepatic decompensation as        defined by the presence of any of the following abnormalities at        Screening:    -   Serum albumin less than 3.5 grams/deciliter (g/dL).    -   An INR greater than 1.1.    -   Direct bilirubin greater than 1.3 milligrams per deciliter        (mg/dL).    -   Subject has a history of bleeding esophageal varices, ascites or        hepatic encephalopathy    -   Subject has a history of hepatitis C. Patients found on        screening to have hepatitis C antibody, even if PCR negative for        HCV RNA, are excluded from this study.    -   Subject has evidence of other forms of chronic liver disease:    -   Hepatitis B as defined by presence of hepatitis B surface        antigen.    -   Evidence of ongoing autoimmune liver disease as defined by        compatible liver histology.    -   Primary biliary cirrhosis as defined by the presence of at least        2 of these criteria (i) Biochemical evidence of cholestasis        based mainly on alkaline phosphatase elevation (ii) Presence of        anti-mitochondrial antibody (iii) Histologic evidence of        nonsuppurative destructive cholangitis and destruction of        interlobular bile ducts.    -   Primary sclerosing cholangitis.    -   Wilson's disease as defined by ceruloplasmin below the limits of        normal and compatible liver histology.    -   Alpha-1-antitrypsin deficiency as defined by diagnostic features        in liver histology (confirmed by alpha-1 antitrypsin level less        than normal; exclusion at the discretion of the study        physician).    -   History of hemochromatosis or iron overload as defined by        presence of 3+ or 4+ stainable iron on liver biopsy.    -   Drug-induced liver disease as defined on the basis of typical        exposure and history.    -   Known bile duct obstruction.    -   Suspected or proven liver cancer.    -   Any other type of liver disease other than NASH.    -   Subject with serum ALT greater than 300 units per liter (U/L) at        Screening.    -   Subject with serum creatinine of 1.5 mg/dL or greater at        Screening.    -   Subject using of any prescription or over-the-counter medication        or herbal remedy that are believed to improve or treat NASH or        liver disease or obesity during the period beginning 30 days        prior to randomization. Subjects who are using Vitamin E or        omega-3 fatty acids may continue their use.    -   Subject had major surgery within 8 weeks prior to Day 0,        significant traumatic injury, or anticipation of need for major        surgical procedure during the course of the study.    -   Subject with a history of biliary diversion.    -   Subject with known positivity for Human Immunodeficiency Virus        infection.    -   Subject with an active, serious medical disease with likely life        expectancy of less than 5 years.    -   Subject with active substance abuse, including inhaled or        injection drugs, in the year prior to Screening.    -   Subject who has clinically significant and uncontrolled        cardiovascular disease (eg, uncontrolled hypertension,        myocardial infarction, unstable angina), New York Heart        Association Grade II or greater congestive heart failure,        serious cardiac arrhythmia requiring medication, or Grade II or        greater peripheral vascular disease within 12 months prior to        Day 0.    -   Subject has participated in an investigational new drug (IND)        trial in the 30 days before randomization.    -   Subject has a clinically significant medical or psychiatric        condition considered a high risk for participation in an        investigational study.    -   Subject has any other condition which, in the opinion of the        Investigator, would impede compliance or hinder completion of        the study.    -   Subject has been previously exposed to GR MD 02.    -   Subject with known allergies to the study drug or any of its        excipients.    -   Subject with malignant disease (other than basal and squamous        cell carcinoma of the skin and in situ carcinoma of the cervix)        with at least 5 years of follow-up showing no recurrence.    -   Subject has an abnormal chest x-ray indicative of acute or        chronic lung disease on screening examination.

Study Design:

-   -   Allocation: Randomized    -   Endpoint Classification: Safety/Efficacy Study    -   Intervention Model: Parallel Assignment    -   Masking: Double Blind (Subject, Investigator)    -   Primary Purpose: Treatment

Primary Outcome Measures:

-   -   The primary objective of this study is to characterize the        safety, which includes the tolerability and dose-limiting        toxicity (DLT), for a combination of an FXR modulator and a        GLP-1 agonist when administered to subjects with biopsy-proven        NASH with advanced liver fibrosis. Specifically, this measure        will be assessed by number of subjects experiencing treatment        emergent adverse events indicative of DLT.

Secondary Outcome Measures:

-   -   A secondary objective is to evaluate change in serum alanine        aminotransferase (ALT), aspartate aminotransferase (AST), ratio        of AST:ALT, alkaline phosphatase, and gamma glutamyl        transpeptidase (GGTP); change in AST/platelet ratio index. [Time        Frame: Baseline; Week 7 (End of Study)] [Designated as safety        issue: No]    -   A secondary objective for this study is to evaluate change in        serum alanine aminotransferase (ALT), aspartate aminotransferase        (AST), ratio of AST:ALT, alkaline phosphatase, and gamma        glutamyl transpeptidase (GGTP) levels; and change in        AST/platelet ratio index.    -   A secondary objective for this study is to evaluate changes in        exploratory pharmacodynamic biomarkers in serum [Time Frame:        Baseline; Week 7 (End of Study)] [Designated as safety issue:        No]    -   A secondary objective for this study is to evaluate levels of        exploratory pharmacodynamic biomarkers in serum including        galectin-3, inflammatory, cell-death, and fibrosis markers.    -   Hepatocellular function as measured by assessment of liver        enzymes and biochemical markers of hepatic and metabolic        function.

This study is a dose ranging study to assess in sequential fashion, thesafety, tolerability, and dose limiting toxicities (DLTs) of acombination of an FXR modulator and a GLP-1 agonist in subjects withbiopsy-proven NASH with advanced fibrosis.

Example 12: Phase 2 Study of Compound 1, Compound 2, or Compound 3 toTreat Primary Biliary Cirrhosis

The purpose of this study is to determine if Compound 1, Compound 2, orCompound 3 has an effect on cholesterol levels in the blood in patientswith primary biliary cirrhosis (PBC).

Study Type: Interventional Study Design: Endpoint Classification:Safety/Efficacy Study Intervention Model: Single Group Assignment

Primary Outcome Measures:

-   -   Change from baseline in High-density lipoprotein (HDL)        Metabolism [Time Frame: Week 4, Week 8 and Week 12] [Designated        as safety issue: No]    -   HDL metabolism will be assessed by measuring HDL cholesterol        concentration, HDL particle size and number.

Secondary Outcome Measures:

-   -   Change from baseline in Lipoprotein Metabolism [Time Frame: Week        4, Week 8 and Week 12] [Designated as safety issue: No]    -   Lipoprotein metabolism will be assessed by measuring the        following:        -   concentrations of total cholesterol and triglycerides        -   Low-density lipoprotein (LDL) and very low density            lipoprotein (VLDL) cholesterol concentrations, particle size            and number        -   concentrations of apolipoprotein A (ApoA), apolipoprotein B            (ApoB), apolipoprotein E (ApoE), and lipoprotein (a) [Lp(a)]    -   Change from baseline Reverse Cholesterol Transport [Time Frame:        Week 4, Week 8 and Week 12] [Designated as safety issue: No]    -   Components of reverse cholesterol transport will also be        assessed as part of the lipoprotein analysis. This will include        measurements of:        -   HDL capacity to accept cholesterol measured by            lecithin-cholesterol acyltransferase (LCAT) and Cholesterol            ester transfer protein (CETP) activity.            -   pre-β1 HDL concentration            -   macrophage cholesterol efflux    -   Pharmacokinetic parameters of Compound 1, Compound 2, or        Compound 3    -   [Time Frame: Week 8] [Designated as safety issue: No]    -   In a subset of patients who agree to participate,        non-compartmental pharmacokinetic parameters of Compound 1,        Compound 2, or Compound 3 will be assessed.

Other Outcome Measures:

-   -   Fasting levels of Compound 1, Compound 2, or Compound 3 [Time        Frame: Week 8] [Designated as safety issue: No]    -   Change from baseline in fibroblast growth factor 19 (FGF-19)        [Time Frame: Week 4, Week 8 and Week 12] [Designated as safety        issue: No]    -   Change from baseline in Lipoprotein X [Time Frame: Week 4, Week        8 and Week 12] [Designated as safety issue: No]    -   Markers of inflammation including: C-Reactive Protein, GlycA and        GlycB [Time Frame: Week 8] [Designated as safety issue: No]

Arms Assigned Interventions Compound 1, Compound 2, Drug: Compound 1,Compound 2, or Compound 3, oral or Compound 3 administration, 8 weeksAll subjects will be treated with Compound 1, Compound 2, or Compound 3(oral administration, 10 mg, once daily) for 8 weeks and should continuetheir prestudy dose of ursodeoxycholic acid (UDCA). After completion ofthe 8 week study period, subjects will be offered the opportunity toenter an open label long term safety extension for up to years.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   Definite or probable primary biliary cirrhosis (PBC) diagnosis        as demonstrated by the presence of ≥2 of the following 3        diagnostic factors:        -   History of elevated alkaline phosphatase (ALP) levels for at            least 6 months        -   A positive anti-microbial antibody (AMA) titer or, if AMA            negative or in low titer (<1:80), PBC specific antibodies        -   Liver biopsy consistent with PBC    -   Taking UDCA for at least 12 months (stable dose for ≥3 months)        prior to Day 0 or unable to tolerate UDCA (no UDCA for ≥3 months        prior to Day 0)    -   Contraception: Female subjects must be postmenopausal,        surgically sterile, or if premenopausal, be prepared to use ≥1        effective (≤1% failure rate) method of contraception during the        trial and until at least 30 days after the last dose of        Investigational Product.

Exclusion Criteria:

-   -   Subjects with decompensated PBC (as determined by the        Investigator)    -   Severe pruritus or systemic treatment for pruritus (e.g.        treatment with bile acid sequestrants or rifampicin) within 2        months of Day 0    -   History or presence of other significant liver diseases        including:        -   Active or chronic Hepatitis B or C virus (HBV, HCV)            infection        -   Primary sclerosing cholangitis (PSC)        -   Alcoholic liver disease        -   Definite autoimmune liver disease or overlap hepatitis        -   Nonalcoholic steatohepatitis (NASH)            -   NOTE: Subjects with Gilbert's disease or those with a                history of hepatitis B who are currently antigen                negative and seroconverted should not be considered                exclusionary    -   Uncontrolled diabetes or other uncontrolled or unstable medical        condition that may interfere with trial results    -   Administration of any of the following medications as specified        below:        -   Prohibited 28 days prior to Day 0: bile acid sequestrants            (BAS) including cholestyramine, colesevelam, or colestipol        -   Prohibited 3 months prior to Day 0 and throughout trial            participation: serum-lipid modifying agents including            3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase            inhibitors, fenofibrate or other fibrates, nicotinic acid            and derivatives, ezetimibe, Vitamin E (other than as            standard dietary supplement), omega-3 fatty acid containing            dietary supplements        -   Prohibited 6 months prior to Day 0 and throughout the trial            participation: azathioprine, colchicine, cyclosporine,            methotrexate, mycophenolate mofetil, pentoxifylline;            budesonide and other systemic corticosteroids; potentially            hepatotoxic drugs (including α-methyl-dopa, sodium valproic            acid, isoniazide, or nitrofurantoin)        -   Prohibited 12 months prior to Day 0 and throughout the trial            participation: antibodies or immunotherapy directed against            interleukins or other cytokines or chemokines    -   Planned change in diet or exercise habits during participation        in the trial    -   Presence or history of clinically significant cardiac        arrhythmias that may prohibit the subject from participating in        the trial If female: known pregnancy, or has a positive urine        pregnancy test (confirmed by a positive serum pregnancy test),        or lactating.

Example 13: Effect of Compound 1, Compound 2, or Compound 3 in theTreatment of Patients with Primary Sclerosing Cholangitis (PSC)

The purpose of this study is to evaluate the effect of Compound 1,Compound 2, or Compound 3 on liver biochemistry, in particular, serumalkaline phosphatase; and, safety.

Study Type: Interventional Study Design: Allocation: Randomized EndpointClassification: Safety/Efficacy Study Intervention Model: Single GroupAssignment Masking: Double Blind (Subject, Caregiver, Investigator)Primary Purpose: Treatment

Primary Outcome Measures:

-   -   Evaluate the effects of Compound on serum alkaline phosphatase        (ALP) in subjects with primary sclerosing cholangitis (PSC)        [Time Frame: 24 weeks] [Designated as safety issue: Yes]    -   Evaluate the effects of Compound on safety in subjects with PSC        [Time Frame: 24 weeks] [Designated as safety issue: Yes]

Secondary Outcome Measures:

-   -   Hepatic biochemistry and indices of function [Time Frame: 24        weeks] [Designated as safety issue: Yes]    -   Hepatic Fibrosis [Time Frame: 24 weeks] [Designated as safety        issue: Yes]    -   Gastrointestinal inflammation and disease [Time Frame: 24 weeks]        [Designated as safety issue: Yes]    -   FXR) activity [Time Frame: 24 weeks] [Designated as safety        issue: Yes]    -   Inflammatory bowel disease (IBD) [Time Frame: 24 weeks]        [Designated as safety issue: Yes]    -   Long-term efficacy [Time Frame: 24 months] [Designated as safety        issue: No]    -   Long term safety [Time Frame: 24 months] [Designated as safety        issue: Yes]    -   Disease-specific symptoms [Time Frame: 24 weeks] [Designated as        safety issue: Yes] Pharmacokinetics (PK) of compound [Time        Frame: 24 Weeks] [Designated as safety issue: No]

Arms Assigned Interventions Experimental: Low dose Compound 1, Drug:Compound 1, Compound 2, Compound 2, or Compound 3 titrating or Compound3 to high dose Compound 1, Compound 2, or Compound 3 Subjects randomizedto low dose will take low dose Compound 1, Compound 2, or Compound 3daily for 12 weeks followed by high dose Compound 1, Compound 2, orCompound 3 for an additional 12 weeks. Experimental: Placebo Drug:Placebo Subjects randomized to placebo will take placebo for 24 weeks

This is a Phase 2, randomized, double-blind, placebo-controlled,dose-finding evaluation of the efficacy and safety of compound insubjects with PSC. Approximately 80 subjects who provide writteninformed consent and meet all of the inclusion and none of the exclusioncriteria will be randomized to 1 of 2 treatment groups as follows: lowdose titrating to high dose Compound 1, Compound 2, or Compound 3, orplacebo, in a 1:1 ratio. Subjects will administer investigationalproduct (IP) orally, once daily for 2 consecutive 12-week periods.

Any subjects whose dose is not titrated, due to safety or tolerabilityconcerns, will remain on their starting treatment (low dose Compound 1,Compound 2, or Compound 3, or placebo) for the remainder of thedouble-blind phase to Week 24.

Randomization will be stratified by the presence or absence ofconcomitant ursodeoxycholic acid (UDCA) use and total bilirubin level(≤1.5× upper limit of normal [ULN] or >1.5×ULN but<2.5×ULN).

Eligibility

Ages Eligible for Study: 18 Years to 75 Years Genders Eligible forStudy: Both Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   Must have a diagnosis of PSC (based on cholangiography at any        point in time) and must have had a cholangiography within the        past 12 months    -   ALP at Screening ≥2×ULN    -   Total bilirubin at Screening <2.5×ULN.    -   For subjects with concomitant IBD:        -   Colonoscopy (if subject has a colon) or other appropriate            endoscopic procedure within 12 months of Day 0 confirming no            dysplasia or colorectal cancer        -   Subjects with Crohn's Disease (CD) must be in remission as            defined by a Crohn's Disease Activity Index (CDAI)<150.        -   Subjects with ulcerative colitis (UC) must either be in            remission or have mild disease. Remission is defined as a            partial Mayo score of ≤2 with no individual sub-score            exceeding 1. Mild disease is defined as a partial Mayo score            ≤3 with no individual sub-score exceeding 1 point.    -   For subjects being administered UDCA as part of their standard        of care, the dose must have been stable for ≥3 months prior to,        and including, Day 0 and must not have exceeded 20 mg/kg/day        during this time.    -   Subjects being administered biologic treatments (eg, anti-tumor        necrosis factor (TNF) or anti-integrin monoclonal antibodies),        immunosuppressants, systemic corticosteroids, or statins, must        have been on a stable dose for ≥3 months prior to, and        including, Day 0 and should plan to remain on a stable dose        throughout the trial.    -   Contraception: female subjects of childbearing potential must        use ≥1 effective method (≤1% failure rate) of contraception        during the trial and until 4 weeks following the last dose of IP        (including long term safety extension doses).

Exclusion Criteria:

-   -   Evidence of a secondary cause of sclerosing cholangitis at        Screening    -   Immunoglobulin G4 (IgG4)>4×ULN at Screening or evidence of IgG4        sclerosing cholangitis    -   Small duct cholangitis in the absence of large duct disease    -   Presence of clinical complications of chronic liver disease or        clinically significant hepatic decompensation, including:    -   Current Child Pugh classification B or C    -   History of, or current diagnosis or suspicion of,        cholangiocarcinoma or other hepatobiliary malignancy, or biliary        tract dysplasia.    -   History of liver transplantation, or current model of end stage        liver disease score ≥12    -   History of, or current, cirrhosis with complications, including        history or presence of spontaneous bacterial peritonitis        hepatocellular carcinoma or hepatic encephalopathy (as assessed        by the investigator)    -   Current known portal hypertension with complications, including        known gastric or large esophageal varices, poorly controlled or        diuretic resistant ascites, history of variceal bleeds, or        related therapeutic or prophylactic interventions (e.g., beta        blockers, insertion of variceal bands or transjugular        intrahepatic portosystemic shunt [TIPS])    -   History of, or current, hepatorenal syndrome (type I or II) or        Screening serum creatinine >2 mg/dL (178 μmol/L)    -   Platelet count <50×10⁹/L    -   Clinical evidence of dominant stricture (as evidenced by        cholangiography or other appropriate imaging modality within the        12 months prior to Day 0) or current biliary stent    -   Current cholecystitis or gallstones (identified by hepatic        imaging)    -   Colonic dysplasia within <5 years prior to Day 0    -   History of small bowel resection    -   History of other chronic liver diseases, including, but not        limited to, primary biliary cirrhosis (PBC), alcoholic liver        disease, non-alcoholic fatty liver disease (NAFLD), autoimmune        hepatitis, hepatitis B virus (unless seroconverted and no        positive Hepatitis B Virus DNA), hepatitis C virus and overlap        syndrome    -   Known Gilbert's syndrome or history of elevations in        unconjugated (indirect) bilirubin >ULN    -   Known history of human immunodeficiency virus (HIV) infection    -   Currently experiencing, or experienced within ≤3 months of        Screening, pruritus requiring systemic or enteral treatment    -   Known or suspected acute cholangitis in the 3 months prior to,        and including, Day 0 including cholangitis treated with        antibiotics    -   Administration of antibiotics is prohibited ≤1 month of Day 0        (unless subject is on a stable prophylaxis dose for at least 3        months prior to Day 0).    -   Administration of the following medications is prohibited ≤6        months of Day 0 and throughout the trial: fenofibrate or other        fibrates and potentially hepatotoxic medications (including        α-methyl-dopa, sodium valproic acid, isoniazide, or        nitrofurantoin).    -   IBD flare during Screening (up to and including Day 0), where        “flare” is defined as follows:        -   UC flare: partial Mayo Score ≥5, and        -   CD flare: CDAI≥250    -   If female: known pregnancy, or has a positive urine pregnancy        test (confirmed by a positive serum pregnancy test), or        lactating    -   Other concomitant disease, malignancy, or condition likely to        significantly decrease life expectancy to less than the duration        of the trial (e.g., moderate to severe congestive heart failure)

Example 14: Use of Compound 1, Compound 2, or Compound 3 for theTreatment of Biliary Atresia

The purpose of this study is to determine whether Compound 1, Compound2, or Compound 3 reduces liver damage in infants with biliary atresia.

Study Type: Interventional Study Design: Endpoint Classification:Efficacy Study Intervention Model: Single Group Assignment Masking: OpenLabel Primary Purpose: Treatment

Primary Outcome Measures:

-   -   Change in serum conjugated bilirubin [Time Frame: Baseline and        after 90 days of therapy] [Designated as safety issue: No]

Secondary Outcome Measures:

-   -   Change in Weight [Time Frame: Baseline and after 90 days of        therapy] [Designated as safety issue: No]    -   Change in serum markers [Time Frame: Baseline and up to two        years after therapy finishes] [Designated as safety issue: No]        The investigators will track the change in serum liver markers        and platelets over the course of two years in patients receiving        90 days of Compound 1, Compound 2, or Compound 3 therapy.    -   Change in liver imaging [Time Frame: Baseline and up to two        years after therapy finishes] [Designated as safety issue: No]        The investigators will track liver ultrasound changes, including        liver and spleen size.    -   Time to liver transplant [Time Frame: Baseline and up to two        years after therapy finishes] [Designated as safety issue: No]

Arms Assigned Interventions Experimental: Compound 1, Compound 2, Drug:Compound 1, Compound 2, or Compound 3 or Compound 3 All newly-diagnosedbiliary atresia 20 mg/kg/day divided in patients fulfilling the study’s3 doses, given orally for inclusion criteria will receive oral 90 daysCompound 1, Compound 2, or Compound 3, 20 mg/kg/day divided in threedoses for a total of 90 days.

Biliary atresia (BA) is a devastating liver disease of infancy ofunknown etiology, characterized by bile duct obstruction, live fibrosis,and cirrhosis. BA has no known medical treatments. The only proventreatment is a surgical portoenterostomy (the Kasai procedure, or KP)which can achieve bile drainage and improve outcomes in some cases. TheKPs success is variable depending on several factors including age ofthe infant, experience of the surgeon, and extent of liver fibrosis atthe time of KP.

In this study, the investigators conduct a phase II trial of a potentialnew medical therapy for BA: Compound 1, Compound 2, or Compound 3. Thetrial's objective is to determine whether Compound 1, Compound 2, orCompound 3 has sufficient biological activity against BA to warrantfurther study. Compound 1, Compound 2, or Compound 3 will beadministered orally for 90 days as an adjunct to standard therapy (i.e.KP if appropriate). The primary outcome will measure the change in serumconjugated bilirubin levels after 90 days. Secondary outcomes includechanges in body weight, serum markers, liver imaging, and time to livertransplant in infants with BA.

Eligibility

Ages Eligible for Study: up to 180 Days Genders Eligible for Study: BothAccepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   Diagnosed with biliary atresia through liver biopsy and/or        intra-operative cholangiogram    -   No previous Kasai portoenterostomy performed at another        institution    -   Able to take medications orally    -   Legal guardian signs consent after understanding risks and        investigational nature of study

Exclusion Criteria:

-   -   Infants greater than 180 days old    -   Infants receiving a Kasai portoenterostomy at another        institution    -   Infants unable to take medications orally

Example 15: Phase 2 Clinical Study of Compound 1, Compound 2, orCompound 3 for Inflammatory Bowel Disease

The purpose of this study is to evaluate the efficacy of the use of oncedaily use of Compound 1, Compound 2, or Compound 3 in subjects withsymptomatic inflammatory bowel disease.

Study Type: Interventional Study Design: Allocation: Randomized EndpointClassification: Efficacy Study Intervention Model: Parallel AssignmentMasking: Double Blind (Subject, Caregiver, Investigator, OutcomesAssessor) Primary Purpose: Treatment

Primary Outcome Measures:

-   -   An increase in the subjects inflammatory bowel disease        questionnaire score [Time Frame: 6 weeks, 12 weeks, and 6        months] [Designated as safety issue: No]        Participants will fill-out a questionnaire called the IBDQ at        enrollment, 6 weeks, 12 weeks, and 6 months after enrollment.        The IBDQ is a validated instrument often used in routine care        and studies of patients with IBD. The IBDQ measures the activity        of IBD and quality of life. It includes 32 questions placed into        4 domains: bowel, social, emotional and systemic. Each question        is ranked from 1-7, 1 being the poorest quality of life and 7        being the best quality of life. A score of >170 means that a        patient is clinically in remission and an increase in score        between 16 and 32 are considered a meaningful improvement in        symptoms.

Arms Assigned Interventions Experimental: Compound 1, Compound 2, Drug:Compound 1, Compound 2, or Compound 3 or Compound 3 daily for 12 weeksSubjects in this arm will receive Compound 1, Compound 2, or Compound 3daily for 12 weeks. Placebo Comparator: Placebo Drug: Placebo Subjectsin this arm will receive a placebo daily for 12 weeks.

The investigators will compare the use of Compound 1, Compound 2, orCompound 3 compared with placebo in subjects that have symptomaticinflammatory bowel disease (IBD). Our subjects will be those withdiagnosed with IBD and are symptomatic, defined by an inflammatory boweldisease questionnaire (IBDQ) score <170. The subjects will be randomlyassigned either placebo or LDN. They will take the IBDQ prior tostarting the trial, 6 weeks, 12 weeks and 6 months after starting themedication. Participants have to remain on their current IBD regimenthroughout the trial and cannot make any changes within 4 weeks ofstarting the trial. The investigators will have a safety phone call at 6weeks and a follow up letter at 12 weeks after starting the trial. Theparticipants will be given a card to keep with them with a phone numberand email address if any adverse effects arise.

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

-   -   Patients with symptomatic Crohn's disease or ulcerative colitis        (defined as a response to the Inflammatory Bowel Disease        Questionnaire less than 170)    -   Confirmed Crohn's disease or ulcerative colitis through        radiographic, endoscopic and/or histologic criteria    -   On a stable dose of medication for IBD (i.e. no change in        medication within 4 weeks of study enrollment)

Exclusion Criteria:

-   -   Patients on opioids or Imodium within 7 days of starting the        investigational therapy    -   Women who are breastfeeding, pregnant, or plan on becoming        pregnant within the next year    -   Women of child bearing age not willing to use contraception or        abstinence    -   A history of the following diseases or procedures:        -   Acute hepatitis        -   Liver failure        -   Ileoanal anastomosis        -   Short bowel syndrome        -   Abnormal liver enzymes

Example 16: Investigation of Compound 1, Compound 2, or Compound 3 inPatients with Irritable Bowel Syndrome

The purpose of this study is to determine if Compound 1, Compound 2, orCompound 3 helps people with irritable bowel syndrome.

Study Type: Interventional

Study Design: Allocation: Randomized

Endpoint Classification: Efficacy Study

Intervention Model: Parallel Assignment

Masking: Double Blind (Subject, Caregiver, Investigator)

Primary Purpose: Treatment

Primary Outcome Measures:

-   -   Primary aim: Collect preliminary data comparing effects of        Compound 1, Compound 2, or Compound 3 and placebo on abdominal        pain/discomfort on bowel symptom score (BSS), overall BSS score,        and adequate relief of irritable bowel syndrome (IBS) symptoms        in patients with IBS [Time Frame: weekly] [Designated as safety        issue: No]

Secondary Outcome Measures:

-   -   To compare the effect of Compound 1, Compound 2, or Compound 3        and placebo on self-reported overall and individual BSS scores        [Time Frame: Last 4 weeks of treatment] [Designated as safety        issue: No]    -   To compare effect of Compound 1, Compound 2, or Compound 3 and        placebo on adequate relief of IBS pain or discomfort at least        50% of the time [Time Frame: During the last 4 weeks of therapy]        [Designated as safety issue: No]    -   To compare effect of Compound 1, Compound 2, or Compound 3 and        placebo on overall and individual BSS scores [Time Frame: Week        12] [Designated as safety issue: No]    -   To compare the effect of Compound 1, Compound 2, or Compound 3        and placebo on the proportion of patients with at least 3 point        changes in 11 point pain and IBS scores [Time Frame: 12 weeks]        [Designated as safety issue: No]

Arms Assigned Interventions Active Comparator: Compound 1, Drug:Compound 1, Compound 2, Compound 2, or Compound 3 or Compound 3 Dose: 75mg twice a day for three days, increasing to 150 mg (2 tablets) twice aday for three days, escalating to 225 mg (three tablets) twice a day,through week 12, day 1. Days 2-4 of week 12, participants will begintapering and will receive 150 mg (two tablets) two times a day and thendays 5-7, participants will receive 75 mg two times a day for theduration of the study. Placebo Comparator: Placebo Drug: PlaceboPlacebo, not active A matching placebo will be administered twice a day

Eligibility

Ages Eligible for Study: 18 Years to 70 Years

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   Established diagnosis of IBS    -   Experience pain with relief with defecation    -   50/100 or greater of pain or discomfort scores during the        two-week baseline period    -   At least three pain attacks in a month, with at least three        episodes of pain intensity equal to or exceeding 50/100

Exclusion Criteria:

-   -   Known alternative/concurrent gastrointestinal diagnosis (e.g.        Crohn's disease, ulcerative colitis, microscopic colitis, active        celiac sprue, chronic pancreatitis or pancreatic insufficiency,        scleroderma, chronic intestinal pseudo-obstruction, bacterial        overgrowth, recent (<6 months) intestinal        bacterial/protozoal/parasitic infections, HIV, active pelvic        floor dysfunction, paraplegia or quadriplegia);    -   Current symptoms of severe depression, as measured by Hospital        Anxiety and Depression Scale (HADS) score (greater or less than        15);    -   Planned surgery (especially transplant) or anesthesia exposure        during trial    -   Are pregnant, lactating, likely to become pregnant during        medication phase and not willing to use a reliable form of        contraception (barrier contraceptives, diaphragm, injections,        intrauterine device, surgical sterilization, or abstinence)    -   Significant acute or chronic progressive neurologic, hepatic,        renal, cardiovascular, respiratory or metabolic disease    -   Recent history of alcohol or substance dependence use or abuse    -   Major cardiovascular events in the last 6 months    -   Use of IBS-specific drugs such as tegaserod (Zelnorm) and        Lotronex (Alosetron) (within 30 days)    -   Participation in another clinical trial (within 30 days)

Example 17: Phase 2 Clinical Study of Compound 1, Compound 2, orCompound 3 for Bile Acid Diarrhea

The investigators propose to develop studies of Compound 1, Compound 2,or Compound 3 in patients with bile acid diarrhea. Preliminary datasuggests that patients with bile acid diarrhea have impaired productionof the ileal hormone Fibroblast Growth Factor 19 (FGF19). FGF19 isstimulated by FXR agonists, and regulates bile acid synthesis. Thisstudy is a pilot, proof-of-concept, open-label study to investigatewhether compound can stimulate FGF19 in bile acid diarrhea patients toprovide a safe and effective treatment.

Study Type: Interventional

Study Design: Endpoint Classification: Pharmacodynamics Study

Intervention Model: Single Group Assignment

Masking: Open Label

Primary Purpose: Treatment

Primary Outcome Measures:

-   -   Fasting FGF19 [Time Frame: 15 days] [Designated as safety issue:        No] The primary outcome measure is the change over 2 weeks in        fasting serum fibroblast growth factor (FGF19) in 3 groups of        patients: primary bile acid diarrhea, secondary bile acid        diarrhea, and a control population of patients with chronic        diarrhea but with normal bile acid retention.

Secondary Outcome Measures:

-   -   Non-fasting response of FGF19 to Compound 1, Compound 2, or        Compound 3 [Time Frame: 15 days] [Designated as safety issue:        No] Change in dynamic response of FGF19 in 6 hours following        Compound 1, Compound 2, or Compound 3 administration; at start        and end of 15 day Compound 1, Compound 2, or Compound 3 test        period.

Arms Assigned Interventions Experimental: Compound 1, Drug: Compound 1,Compound 2, Compound 2, or Compound 3 or Compound 3 25 mg, once dailyfor 15 days. Day-14 to Day 0 subjects will stop their usual diarrhealmedication. Day 1 to Day 15 Compound 1, Compound 2, or Compound 3 25 mgtablet will be administered to subjects once daily in the morning. Day16 to day 28 normal diarrheal medication may be re-commenced.

Bile acid diarrhea (BAD) is an under-recognized but common condition ofchronic watery diarrhea. BAD may be secondary to ileal disease affectingthe reabsorption and the enterohepatic circulation of bile acids (bileacid malabsorption) or can be an idiopathic, primary BAD (PBAD).

Blood levels of the hormone fibroblast growth factor 19 (FGF19) arereduced in primary and secondary BAD, producing impaired feedbackinhibition of bile acid synthesis, leading to excess faecal bile acids,which then produce diarrhea by stimulating colonic secretion. FGF19 issynthesised in the ileum and we have shown transcription is markedlyinduced by farnesoid X receptor (FXR) agonists such as chenodeoxycholicacid, an abundant natural bile acid.

We aim to investigate the effects of Compound 1, Compound 2, or Compound3 in patients with primary and secondary BAD to determine whether FGF19is able to be stimulated in these conditions. We will compare theseresponses to those in control patients with chronic diarrhea but withoutevidence of BAD. It is possible in BAD that the defect in FGF19 levelsis due to an inability to respond to FXR stimulation (particularlylikely in secondary BAD after ileal resection). Patients with primaryBAD may be able to respond and benefit from an increase in FGF19 levels.

This study aims to obtain pilot data on the effects of Compound 1,Compound 2, or Compound 3 on FGF19, other markers of bile acidmetabolism and patient symptoms including diarrhea.

Eligibility

Ages Eligible for Study: 18 Years to 80 Years

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

-   -   Patients who present with chronic diarrhea, defined as an        average stool frequency of at least three per day, of Bristol        Stool Type 6 or 7, for at least 3 months. Previous routine        SeHCAT testing to establish the presence or absence of bile acid        diarrhea (BAD) unless there is evidence of TI disease/resection.        BAD will be defined as SeHCAT 7-day retention of less than 15%        or diarrhea in presence of TI disease/resection. Study subjects        will be grouped as having secondary BAD, due to ileal resection        or Crohn's disease, or primary BAD, with no obvious cause. The        third, control group having chronic diarrhea but with normal        SeHCAT retention (greater than 15%).    -   Female patients must be postmenopausal, surgically sterile, or        if premenopausal, be prepared to use ≥1 effective (≤1% failure        rate) method of contraception during the trial and for 15 days        after the last dose of Compound 1, Compound 2, or Compound 3.        Male subjects with female partners of childbearing potential        must use ≥1 effective method of contraception.

Exclusion Criteria

-   -   Patients with other diagnoses leading to diarrhea, including        colorectal neoplasia, ulcerative colitis, coeliac disease,        chronic pancreatitis, drug-induced diarrhea or active infection.    -   Patients who have not been investigated by standard clinical        assessments to exclude these disorders.    -   Treatment with bile acid sequestrants (colestyramine,        colestipol, colesevelam) for 2 weeks before the first dose of        Compound 1, Compound 2, or Compound 3.    -   Previous biliary surgery, excluding cholecystectomy.    -   Abnormal bilirubin, alanine aminotransferase (ALT), aspartate        aminotransferase (AST) or alkaline phosphatase on more than 1        occasion.    -   Chronic liver disease    -   Chronic kidney disease    -   Active, serious medical disease with likely life expectancy less        than 5 years    -   Active substance abuse including inhaled or injection drugs in        the year prior to screening    -   Pregnancy, planned pregnancy, potential for pregnancy and        unwillingness to use effective birth control during the trial,        breast feeding. Pregnancy will be assessed with urinary β-hCG        pregnancy test.

Example 18: Use of Compound 1, Compound 2, or Compound 3 for theTreatment of Hepatic Fibrosis in Chronic Viral Hepatitis B

The purpose of this study is to explore the effective dose and safety ofCompound 1, Compound 2, or Compound 3 on hepatic fibrosis in chronicviral hepatitis B.

Study Type: Interventional Study Design: Allocation: Randomized EndpointClassification: Safety/Efficacy Study Intervention Model: ParallelAssignment Masking: Double Blind (Subject, Caregiver, Investigator,Outcomes Assessor) Primary Purpose: Treatment

Primary Outcome Measures:

-   -   Changes in hepatic fibrosis in chronic viral hepatitis B [Time        Frame: one year] [Designated as safety issue: Yes]

Arms Assigned Interventions Experimental: Compound 1, Drug: Compound 1,Compound 2, or Compound 2, or Compound 3 Compound 3 & Placebo Theinvestigational products in the test groups and control group shall beorally taken 30 minutes before meals for 52 continuous weeks. There arerespectively 60 cases in the test group I, II, III and the controlgroup, totally 240 cases.

Primary Observation Indexes:

-   -   Hepatic fibrosis Ishak score after treatment decreases by the        proportion not less than 1 compared with that before treatment.

Secondary Observation Indexes:

-   -   Negative conversion ratio of HBV DNA after treatment (HBV        DNA<1×103copies/mL) and falling range.    -   The falling proportion of Fibrocan Kpa value after treatment        compared with that before treatment.    -   The falling proportion that decreases not less than 1 level and        progression-free fibrosis after treatment compared with that        before treatment.    -   The improvement of ALT of liver function.

Eligibility

Ages Eligible for Study: 18 Years to 65 Years Genders Eligible forStudy: Both Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   History of chronic hepatitis B, HBsAg positive six months.    -   ALT<five-fold ULN (maximum).    -   Significant liver fibrosis confirmed by liver biopsy.    -   HBeAg positive patients, HBV DNA>2.0×104 IU/mL (copies/mL);        HBeAg negative patients' HBV DNA>2.0×103 IU/mL (104copies/mL).    -   Having not accepted the antiviral therapy with interferon and/or        nucleoside analog.    -   Having not taken anti-inflammatory drugs to protect liver within        1 month before selection.    -   Capable of understanding and signing the informed consent before        the study.

Exclusion Criteria:

-   -   Failing to meet any one requirement of the inclusion criteria.    -   Having suffered massive hemorrhage of gastrointestinal tract        within 3 months before selection    -   TBiL>three-fold ULN.    -   AFP>50 ug/L    -   PLT≤60000 ug/L    -   Having obvious space-occupying lesion in liver as shown by B        ultrasound examination.    -   With a portal vein ≥1.2 cm wide as shown by B ultrasound        examination.    -   BMI index >30.    -   The patient who suffered from liver function decompensation        hepatic cirrhosis and liver neoplasms.    -   The patient with alcoholic, drug-induced, hereditary, immune and        other viral and non-viral chronic hepatitis.    -   The patient with angiocarpy, lung, kidney, incretion, nerve and        blood system disease and mental disease.    -   The patient with active peptic ulcer.    -   Gestational and breast feeding women.    -   The subject who participated in other drug tests within recent 3        months.

Example 19: Phase 2 Study of Compound 1, Compound 2, or Compound 3 inthe Treatment of Gallstone Patients

The purpose of this study is to explore the effects of Compound 1,Compound 2, or Compound 3 on Hepatic Fatty Acid/Triglyceride Metabolismand Hepatobiliary Detoxification/Elimination in Gallstone Patients.

Study Type: Interventional Study Design: Allocation: Randomized EndpointClassification: Pharmacodynamics Study Intervention Model: ParallelAssignment Masking: Double Blind (Subject, Investigator) PrimaryPurpose: Basic Science

Primary Outcome Measures:

-   -   Effects of Compound 1, Compound 2, or Compound 3 on        FXR-dependent metabolism [Time Frame: Day 21] [Designated as        safety issue: No]

Primary Endpoints

-   -   relative changes in markers for insulin resistance    -   relative changes in FA and TG    -   relative changes in hepatic and adipose tissue lipase expression        and activity    -   relative changes in hepatic apical transport proteins ABCG5/8,        BSEP, MDR3, MRP2    -   relative changes in hepatic ER stress markers

Secondary Outcome Measures:

-   -   Effects of Compound 1, Compound 2, or Compound 3 on serum lipid        levels [Time Frame: 21 days] [Designated as safety issue: No]

Secondary Endpoints

-   -   relative changes in total cholesterol, LDL-C, HDL-C, Apo A1, Apo        B, in Lp(A)

Arms Assigned Interventions Active Comparator: Compound 1, Drug:Compound 1, Compound 2, Compound 2, or Compound 3, or Compound 3, 25mg/day 25 mg/day in three weeks in three weeks Placebo Comparator:Gallstone Drug: Placebo Placebo

In a placebo-controlled double-blind randomized trial, healthy gallstonepatients will be administered 25 mg/day Compound 1, Compound 2, orCompound 3 or placebo for three weeks until the day before surgery.Gallbladder bile will be sampled for the measurements of biliary lipids(cholesterol, phospholipids, bile acids) and the calculation of thecholesterol saturation index.

Eligibility

Ages Eligible for Study: 20 Years to 65 Years Genders Eligible forStudy: Both Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   symptomatic, ultrasound verified gallstone disease

Exclusion Criteria:

-   -   Chronic liver disease other than NAFLD (viral hepatitis,        autoimmune liver disease, hemochromatosis, homozygous        alpha1-antitrypsin deficiency and Wilson disease)    -   Previous gastric or small bowel surgery    -   Inflammatory bowel disease    -   Uncontrolled diabetes mellitus (fasting blood glucose >6.7        mmol/L), hypothyroidism or hyperthyroidism, or other significant        endocrine disease.    -   Pregnancy. A urine pregnancy test will be performed the day        before start of medication. Women of childbearing potential can        only be included if a safe and reliable contraception is used,        e.g., oral contraceptives.    -   Elevations of transaminases (ALAT/ASAT) or alkaline phosphatase        or bilirubin above 2×ULN (upper limit of normal) the day before        start of medication.    -   Other serious disease, including depressive disorders treated by        medication

Example 20: Study of Compound 1, Compound 2, or Compound 3 to TreatFocal Segmental Glomerulosclerosis (FS GS)

The purpose of this study is to assess the safety and tolerability ofCompound 1, Compound 2, or Compound 3 in patients with FSGS and toconduct a pharmacokinetic (PK) assessment of Compound 1, Compound 2, orCompound 3 to enable selection of medication regimens for investigationin a randomized Phase II study.

Study Type: Interventional

Study Design: Allocation: Randomized

Endpoint Classification: Safety Study

Intervention Model: Parallel Assignment

Masking: Open Label

Primary Purpose: Treatment

Primary Outcome Measures:

-   -   Safety and tolerance of medications [Time Frame: 16 week        treatment period]

Secondary Outcome Measures:

-   -   Reduction in proteinuria [Time Frame: 16 week treatment period]

Arms Assigned Interventions Compound 1, Compound 2, or Compound 3 Drug:compound oral drug administration

Eligibility

Ages Eligible for Study: 2 Years to 40 Years

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   Estimated glomerular filtration rate (GFR)≥40 ml/min/1.73 m2 at        most recent measurement prior to randomization        -   For patients <age 18 years: Schwartz formula        -   For patients ≥age 18 years: Cockroft-Gault formula    -   Up/c>1.0 g/g creatinine on first morning void at time of        randomization    -   Biopsy confirmed as primary FSGS (including all subtypes) by        study pathologist.    -   Steroid resistance: During the last treatment course with high        dose steroids prior to randomization, the patient must have        demonstrated steroid resistance defined below and not have had a        complete remission of proteinuria (Up/c<0.2 or dipstick urine        protein negative/trace) subsequently. The course of steroid        treatment that defines resistance must be the same or equivalent        to at least 4 weeks of every day dosing with a minimum        cumulative dose of 56 mg/kg or 1680 mg of prednisone or its        equivalent.    -   May be taking angiotensin-converting enzyme inhibitor (ACEI),        angiotensin receptor blocking agent (ARB), vitamin E, or lipid        lowering therapy    -   Willingness to comply with clinical trial protocol, medications,        and follow-up visits, etc.    -   Screen failure in FSGS-CT based on prior treatment with excluded        medication    -   Treatment failure in FSGS-CT based on failure to achieve        remission after 26 weeks or 52 weeks of test therapy, i.e.,        cyclosporine or mycophenolate mofetil (MMF)+oral dexamethasone        pulses

Exclusion Criteria

-   -   Secondary FSGS    -   Treated with cyclophosphamide, chlorambucil, levamisole,        methotrexate, nitrogen mustard, or other immunosuppressive        medications in the 30 days prior to randomization    -   Lactation, pregnancy, or refusal of birth control in women of        child bearing potential    -   Participation in another therapeutic trial concurrently or for        30 days prior to randomization    -   Active/serious infection (including, but not limited to        hepatitis B or C, HIV)    -   Malignancy    -   Systemic lupus erythematosus (SLE) or multiple sclerosis    -   Hepatic disease defined as serum AST/ALT>2.5× the upper limit of        normal    -   Patients with blood pressure >140/95 or >95th percentile for        age/height while receiving maximal doses of 3 or more        antihypertensive agents.    -   Diabetes mellitus (DM) type I or II.    -   Hematocrit <30%    -   Organ transplantation    -   Obesity (based on estimated dry weight at disease onset prior to        steroid therapy) defined as:        -   Body mass index (BMI)>97th percentile for age if aged 2-20            years        -   BMI>40 kg/m2 if aged ≥21 years    -   Allergy to study medications    -   Inability to consent/assent

Example 21: Effect of Compound 1, Compound 2, or Compound 3 in theTreatment of Patients with Hypertriglyceridemia

The proposed study will utilize several different measures oflipoprotein structure and function. The investigators will measurefunctional parameters such as the binding affinity of lipoproteinsbefore and after treatment with Compound 1, Compound 2, or Compound 3.The investigators will also measure fatty acid, oxylipin andapolipoprotein content of plasma, very-low-density lipoprotein (VLDL),low-density lipoprotein (LDL) and high-density lipoprotein (HDL).

Study Design: Endpoint Classification: Efficacy Study InterventionModel: Single Group Assignment Masking: Open Label Primary Purpose:Treatment Study Type: Interventional

Primary Outcome Measures:

-   -   The primary endpoint will be the effect of treatment on        lipoprotein binding to target cells. [Time Frame: one year]        [Designated as safety issue: No]

Secondary Outcome Measures:

-   -   Performance of VLDL as a substrate for lipolysis. [Time Frame:        one year] [Designated as safety issue: No]    -   Plasma LpL mass and activity. [Time Frame: one year] [Designated        as safety issue: No]    -   VLDL, LDL, HDL oxylipin and fatty acid content [Time Frame: one        year] [Designated as safety issue: No]

Arms Assigned Interventions Experimental: Compound 1, Drug: Compound 1,Compound 2, Compound 2, or Compound 3 or Compound 3 1 gram gel capsule 4capsules per day for 8 weeks

Eligibility

Ages Eligible for Study: 18 Years to 79 Years Genders Eligible forStudy: Both Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   Good health by medical history, physical exam,        electrocardiogram, laboratory test (e.g., serum chem.,        urinalysis)    -   Mean fasting serum triglyceride of two most recent tests in        medical record ≥200 and <500 mg/dL    -   Mean LDL-cholesterol of two most recent tests in medical record        ≤1.1×NCEP ATP III goal

Exclusion Criteria:

-   -   Medications, vitamin pills, nutritional supplements or herbal        preparations deemed exclusionary per primary investigator for        possible interference    -   Poorly controlled diabetes mellitus (e.g. [HbA1c]>8.0%)    -   History of a cardiovascular event    -   Past revascularization procedure    -   Past aortic aneurysm or an aortic dissection <6 months prior to        screening    -   History of pancreatitis    -   Poorly controlled hypertension (i.e.: >=160 systolic (resting)        and/or >=100 diastolic (resting)) at 2 consecutive visits    -   Serum Creatinine >2.0 mg/dL    -   Serum transaminase >1.5× upper limit of normal (ULN); including        aspartate aminotransferase [AST] or alanine aminotransferase        [ALT]; 31 U/L for AST, 45 U/L for ALT    -   Creatine Kinase (CK)>3.0×ULN    -   Women who are pregnant or nursing

Example 22: Study of Compound 1, Compound 2, or Compound 3 to TreatDiabetic Nephropathy

The purpose of this study is to evaluate the safety and effects ofCompound 1, Compound 2, or Compound 3 in treatment of diabeticnephropathy.

Study Type: Interventional Study Design: Allocation: Randomized EndpointClassification: Safety/Efficacy Study Intervention Model: ParallelAssignment Masking: Double Blind (Subject, Caregiver, Investigator,Outcomes Assessor) Primary Purpose: Treatment

Primary Outcome Measures:

-   -   Urine albumin level [Time Frame: 3 months] [Designated as safety        issue: Yes]    -   Serum creatinin [Time Frame: 3 months] [Designated as safety        issue: Yes]

Secondary Outcome Measures:

-   -   Fasting blood sugar (FBS) [Time Frame: 3 months] [Designated as        safety issue: Yes]    -   Glycosylated hemoglobin (A1C) [Time Frame: 3 months] [Designated        as safety issue: Yes]    -   Liver aminotransferases (ALT and AST) [Time Frame: 3 months]        [Designated as safety issue: Yes]    -   Serum insulin level [Time Frame: 3 months] [Designated as safety        issue: Yes]    -   Number of patients with adverse events [Time Frame: 3 months]        [Designated as safety issue: Yes]

Arms Assigned Interventions Experimental: Compound 1, Drug: Compound 1,Compound 2, or Compound 2, or Compound 3 Compound 3 Compound 1, Compound2, or Compound 3; 500 mg daily Placebo Comparator: Placebo Drug: PlaceboPlacebo Placebo 1 capsule daily

Eligibility

Ages Eligible for Study: 18 Years to 70 Years Genders Eligible forStudy: Both Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   Type 2 diabetes mellitus (DM)    -   Controlled blood sugar [fasting blood sugar (FBS)<130 mg/dl and        glycosylated hemoglobin (A1C)<7%    -   Urine albumin >20 mg/lit in two separate occasions during the        last 3 months period    -   Serum creatinin < or =2 mg/dl

Exclusion Criteria:

-   -   Pregnancy    -   Lactation    -   Alcoholism    -   Liver failure (acute or chronic)    -   Renal failure: serum creatinin >2 mg/dl    -   Glomerulonephritis    -   Uncontrolled hypertension    -   Congestive heart failure    -   Prostate disease    -   Malignancy    -   Bilateral renal artery stenosis    -   Any infection or rheumatologic disorder

Example 23: Phase 2 Study of Compound 1, Compound 2, or Compound 3 inthe Treatment of Patients with Atherosclerosis

The purpose of this study is to assess the effect of Compound 1,Compound 2, or Compound 3 on the reduction of atherosclerosis in thecarotid artery will be assessed using carotid ultrasound.

Study Type: Interventional Study Design: Allocation: Randomized EndpointClassification: Safety/Efficacy Study Intervention Model: ParallelAssignment Masking: Double-Blind Primary Purpose: Treatment

Primary Outcome Measures:

-   -   Efficacy of Compound 1, Compound 2, or Compound 3 versus placebo        on the progression of atherosclerosis

Secondary Outcome Measures:

-   -   Safety and tolerability of Compound 1, Compound 2, or Compound 3        versus placebo in patients with atherosclerosis

Eligibility

Ages Eligible for Study: 30 Years to 75 Years Genders Eligible forStudy: Both Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   Increased cardiovascular risk (i.e. history of myocardial        infarction, stroke, diabetes mellitus, left ventricular        hypertrophy)    -   Intima-media thickness greater than or equal to 0.8 mm as        measured by ultrasonography    -   Negative pregnancy test for females

Exclusion Criteria:

-   -   Whole blood donation (greater than or equal to 450 ml) during        the last three months before study start    -   Unstable angina, congestive heart failure or uncontrolled        hypertension    -   Renal disease including nephrectomy and/or renal transplant    -   Hepatic disease or abnormal liver function parameters    -   Drug abuse or alcohol addiction

Example 24: Use of Compound 1, Compound 2, or Compound 3 for theTreatment of Portal Hypertension

The purpose of this study is to determine the efficacy and safety ofCompound 1, Compound 2, or Compound 3 as compared to placebo forlowering portal hypertension.

Study Type: Interventional

Study Design: Allocation: Randomized

Endpoint Classification: Safety/Efficacy Study

Intervention Model: Parallel Assignment

Masking: Double Blind (Subject, Investigator)

Primary Purpose: Treatment

Primary Outcome Measures:

-   -   Change From Baseline in Hepatic Venous Pressure Gradient (HVPG)        After Four (4) Weeks of Treatment [Time Frame: 4 weeks]        [Designated as safety issue: No]

Arms Assigned Interventions Placebo Comparator: Placebo Drug: Placebocapsules three times Placebo daily (TID) Experimental: Compound 1, Drug:Compound 1, Compound 2, Compound 2, or Compound 3 or Compound 3 Compound1, Compound 2, or Compound 3 (capsules) three times daily (TID

Eligibility

Ages Eligible for Study: 18 Years and older

Genders Eligible for Study: Both

Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

-   -   Patient has clinical and/or pathological diagnosis of        intra-hepatic portal hypertension.    -   Patient has clinical diagnosis of cirrhosis.    -   Patient has undergone variceal banding.

Exclusion Criteria:

-   -   Patient has a Child-Pugh score >12.    -   Patient has portal hypertension resulting from hepatic vein        obstruction, portal vein occlusion, schistosomiasis, portal vein        thrombosis, splenic vein thrombosis, or Budd-Chiari syndrome.    -   Variceal banding procedure was performed within 1 month of the        screening visit.    -   Patient has active or recurrent variceal bleeding, or has had        variceal bleeding within the 12 weeks prior to screening.    -   Patient is unwilling to discontinue use of vasoactive drugs from        the screening visit through the end of the study.    -   Patient has hepatocellular carcinoma that is being medically        treated or is advanced.    -   Patient has impaired renal function (i.e., serum creatinine        concentration >1.8 mg/dl)    -   Patient has a history of liver transplant, or is expected to        receive a liver transplant during the study period.    -   Patient has undergone a gastrointestinal or abdominal surgical        procedure within 90 days prior to the Screening Visit, or has        had a bowel resection at any time.

The examples and embodiments described herein are for illustrativepurposes only and in some embodiments, various modifications or changesare to be included within the purview of disclosure and scope of theappended claims.

1. A method of treating a metabolic disorder in a subject in needthereof, comprising co-administering to the subject a therapeuticallyeffective amount of: (a) a first agent that is an FXR modulator; and (b)at least one second agent that is an CCR2/CCR5 antagonist, ASK1inhibitor, DPP-IV inhibitor, caspase protease inhibitor, SGLT2inhibitor, acetyl-CoA carboxylase (ACC) inhibitor, diacylglycerolacyltransferase-1 inhibitor, sodium-bile acid cotransporter-inhibitor,TLR-4 antagonist, PPAR alpha/delta agonist, or GLP-1 agonist, or acombination thereof; wherein the FXR modulator is a compound selectedfrom the Formula (I):

wherein: R¹ is selected from the group consisting of hydrogen, halogen,optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,optionally substituted C₂-C₆alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted—(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,—N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,—C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,—C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,—C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵; R² is selected fromthe group consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedheteroaryl, optionally substituted C₂-C₉heterocycloalkyl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl); R³ is selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedheteroaryl, optionally substituted C₂-C₉heterocycloalkyl, optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰,—S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,—C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,—N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,—N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and—P(O)(OR¹⁹)OR²⁰; R⁴ and R⁵ are each independently selected from thegroup consisting of hydrogen, halogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₂-C₆alkenyl, and optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵together with the carbon atom to which they are attached, form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring; R⁶ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and—C(O)N(R²⁷)R²⁸; R⁷ is selected from the group consisting of hydrogen,halogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionallysubstituted C₂-C₆alkynyl; R⁸ is selected from the group consisting of—CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

R⁹ is selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionallysubstituted C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); or R⁸ and R⁹ together with the carbonatoms to which they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring;R¹⁰, R¹³ and R¹⁴ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl); R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionallysubstituted C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together withthe nitrogen atom to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring; R¹⁵ is selected from the groupconsisting of optionally substituted C₁-C₆alkyl, optionally substitutedC₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, optionallysubstituted C₃-C₈ cycloalkyl, optionally substituted aryl optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl); R¹⁹, R²⁰, and R²³ are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionallysubstituted C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); R²¹ and R²² are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl); oroptionally R²¹ and R²² together with the nitrogen atom to which they areattached, form an optionally substituted C₂-C₉heterocycloalkyl ring; R²⁴is selected from the group consisting of optionally substitutedC₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted aryl optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl);and R²⁵ and R²⁶ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₃-C₈cycloalkyl, optionally substituted aryl, optionallysubstituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl); or a pharmaceuticallyacceptable salt, stereoisomer or solvate thereof; R²⁷ and R²⁸ are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); or R²⁷ and R²⁸ together with the nitrogenatom to which they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring; or a pharmaceutically acceptable salt,stereoisomer or solvate thereof; wherein the metabolic disorder isnonalcoholic steatohepatitis (NASH), hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, dyslipidemia, lipodystrophy,atherosclerosis, atherosclerotic disease, atherosclerotic diseaseevents, atherosclerotic cardiovascular disease, Syndrome X, diabetesmellitus, type II diabetes, insulin insensitivity, hyperglycemia,cholestasis, obesity, diabetic nephropathy or nephrotic syndrome.
 2. Themethod of claim 1, wherein the FXR modulator is a compound of Formula(III):

wherein: R¹ is selected from the group consisting of hydrogen, halogen,optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,optionally substituted C₂-C₆alkynyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₃-C₈cycloalkyl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted—(C₁-C₂alkylene)-(C₂-C₉heterocycloalkyl), optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted—(C₁-C₂alkylene)-(heteroaryl), —OR¹⁰, —SR¹⁰, —N(R¹¹)R¹²,—N(R¹¹)S(O)₂R¹⁵; —N(R¹³)N(R¹¹)R¹², —N(R¹³)N(R¹¹)S(O)₂R¹⁵, —C(O)R¹⁴,—C(O)OR¹⁰, —C(S)OR¹⁰, —C(O)SR¹⁰, —C(O)N(R¹¹)R¹², —C(S)N(R¹¹)R¹²,—C(O)N(R¹¹)S(O)₂R¹⁵, —C(S)N(R¹¹)S(O)₂R¹⁵, —C(O)N(R¹³)N(R¹¹)R¹²,—C(S)N(R¹³)N(R¹¹)R¹² and —C(O)N(R¹³)N(R¹¹)S(O)₂R¹⁵; R⁴ and R⁵ are eachindependently optionally substituted C₁-C₆alkyl; R⁹ is selected from thegroup consisting of hydrogen, optionally substituted C₁-C₆alkyl,optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl);R¹⁰, R¹³ and R¹⁴ are each independently selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl); R¹⁵ is selected from thegroup consisting of optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted C₃-C₈ cycloalkyl, optionally substituted aryloptionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedC₂-C₉heterocycloalkyl, optionally substituted heteroaryl, and optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl); R¹¹ and R¹² are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionallysubstituted C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); or optionally R¹¹ and R¹² together withthe nitrogen atom to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring; R²⁵ is C₁-C₆alkyl; R³⁰ ishalogen,

each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl; eachR³² and R³³ are each independently selected from the group consisting ofhydrogen, halogen, and C₁-C₆alkyl; R³⁴ and R³⁵ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, and optionallysubstituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with thenitrogen atom to which they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring;n is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; t is 2, 3, or 4; or apharmaceutically acceptable salt, stereoisomer or solvate thereof. 3.The method of claim 1, wherein the FXR modulator is a compound havingthe structure:

or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.4. (canceled)
 5. The method of claim 1, wherein the second agent is anCCR2/CCR5 antagonist selected from the group consisting of cenicriviroc(CVC), apiaviroc, vicriviroc, maraviroc and cochilioquinone.
 6. Themethod of claim 1, wherein the second agent is an ASK1 inhibitorselected from the group consisting of GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide) and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride).
 7. The method of claim 1, wherein the second agent isa DPP-IV inhibitor selected from the group consisting of sitagliptin,saxagliptin, linagliptin, alogliptin, vildagliptin, gemigliptin,anagliptin, teneligliptin, trelagliptin, dutogliptin and omarigliptin.8. The method of claim 1, wherein the second agent is a caspase proteaseinhibitor selected from the group consisting of emricasan, Q-VD-Oph,DEVD-CHO, zVAD-FMK, Pralnacasan and M867.
 9. The method of claim 1,wherein the second agent is an SGLT2 inhibitor selected from the groupconsisting of canagliflozin, empagliflozin, dapagliflozin,ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozinetabonate and ertugliflozin.
 10. The method of claim 1, wherein thesecond agent is a GLP-1 agonist selected from the group consisting ofexenatide, liraglutide, lixisenatide, albiglutide, dulaglutide,taspoglutide, and semaglutide. 11.-15. (canceled)
 16. A method oftreating a metabolic disorder in a subject in need thereof, comprisingco-administering to the subject a therapeutically effective amount of:(a) a first agent that is an FXR modulator; and (b) at least one secondagent that is an CCR2/CCR5 antagonist, ASK1 inhibitor, DPP-IV inhibitor,caspase protease inhibitor, SGLT2 inhibitor, acetyl-CoA carboxylase(ACC) inhibitor, diacylglycerol acyltransferase-1 inhibitor, sodium-bileacid cotransporter-inhibitor, TLR-4 antagonist, PPAR alpha/deltaagonist, or GLP-1 agonist, or a combination thereof; wherein the FXRmodulator is a compound of Formula (VII):

wherein: R¹ is selected from the group consisting of hydrogen,optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,optionally substituted C₂-C₆alkynyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); R² is selected from the group consistingof —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

 or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring; R³ is selected from the groupconsisting of hydrogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl,optionally substituted C₃-C₈cycloalkyl, optionally substituted aryl,optionally substituted —(C₁-C₂alkylene)-(aryl), optionally substitutedheteroaryl, optionally substituted C₂-C₉heterocycloalkyl, optionallysubstituted —(C₁-C₂alkylene)-(heteroaryl), —C(O)R²⁰, —C(O)OR²⁰,—S(O)₂R²⁰, —C(O)N(R²¹)R²², —C(O)N(R²¹)S(O)₂R²⁴, —C(O)N(R²³)N(R²¹)R²²,—C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)R²⁰, —N(R²³)C(O)N(R²¹)R²²,—N(R²³)C(O)N(R²¹)S(O)₂R²⁴, —N(R²⁰)C(O)N(R²³)N(R²¹)R²²,—N(R²⁰)C(O)N(R²³)N(R²¹)S(O)₂R²⁴, —N(R²³)C(O)OR²⁰, —P(O)OR²⁰, and—P(O)(OR¹⁹)OR²⁰; R⁴ and R⁵ are each independently selected from thegroup consisting of hydrogen, halogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionally substitutedC₂-C₆alkenyl, and optionally substituted C₂-C₆alkynyl; or R⁴ and R⁵together with the carbon atom to which they are attached, form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring; R⁶ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and—C(O)N(R²⁷)R²⁸; R⁷ is selected from the group consisting of hydrogen,halogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionallysubstituted C₂-C₆alkynyl; R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); R⁹ and R¹⁰ together with the carbon atomsto which they are attached, form an optionally substituted nitrogencontaining 6-membered heteroaryl ring; R¹⁹, R²⁰, and R²³ are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionallysubstituted C₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); R²¹ and R²² are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl); orR²¹ and R²² together with the nitrogen atom to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring; R²⁴ isselected from the group consisting of optionally substituted C₁-C₆alkyl,optionally substituted C₂-C₆alkenyl, optionally substitutedC₂-C₆alkynyl, optionally substituted C₃-C₈ cycloalkyl, optionallysubstituted aryl optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl);R²⁵ and R²⁶ are each independently selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); and R²⁷ and R²⁸ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl); orR²⁷ and R²⁸ together with the nitrogen atom to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring; or apharmaceutically acceptable salt, stereoisomer or solvate thereof;wherein the metabolic disorder is nonalcoholic steatohepatitis (NASH),hyperlipidemia, hypercholesterolemia, hypertriglyceridemia,dyslipidemia, lipodystrophy, atherosclerosis, atherosclerotic disease,atherosclerotic disease events, atherosclerotic cardiovascular disease,Syndrome X, diabetes mellitus, type II diabetes, insulin insensitivity,hyperglycemia, cholestasis, obesity, diabetic nephropathy or nephroticsyndrome.
 17. The method of claim 16, wherein the FXR modulator is acompound of Formula (VIId), or a pharmaceutically acceptable salt,stereoisomer or solvate thereof:

wherein: each R¹¹ is independently selected from the group consisting ofhalogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl, C₂-C₉heterocycloalkyl,aryl, heteroaryl, —C(O)OR¹², and —C(O)N(R¹³)R¹⁴; each R¹² isindependently selected from the group consisting of hydrogen andC₁-C₆alkyl; each R¹³ and R¹⁴ are each independently selected from thegroup consisting of hydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ togetherwith the nitrogen atom to which they are attached, form an optionallysubstituted C₂-C₉heterocycloalkyl ring; and n is 0, 1, 2, or
 3. 18. Themethod of claim 16, wherein the FXR modulator is a compound of Formula(VIII):

wherein: R¹ is selected from the group consisting of hydrogen,optionally substituted C₁-C₆alkyl, optionally substituted C₂-C₆alkenyl,optionally substituted C₂-C₆alkynyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); R² is selected from the group consistingof —CN, —C(O)OR²⁵, —C(O)N(R²⁵)R²⁶,

 or R¹ and R² together with the carbon atoms to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring or anoptionally substituted heteroaryl ring; R⁴ and R⁵ are each independentlyselected from the group consisting of hydrogen, halogen, optionallysubstituted C₁-C₆alkoxy, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, and optionally substituted C₂-C₆alkynyl; or R⁴and R⁵ together with the carbon atom to which they are attached, form anoptionally substituted C₃-C₆cycloalkyl ring or an optionally substitutedC₂-C₇heterocycloalkyl ring; R⁶ is selected from the group consisting ofhydrogen, halogen, optionally substituted C₁-C₆alkyl, optionallysubstituted C₂-C₆alkenyl, optionally substituted C₂-C₆alkynyl, and—C(O)N(R²⁷)R²⁸; R⁷ is selected from the group consisting of hydrogen,halogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₁-C₆alkoxy, optionally substituted C₂-C₆alkenyl, and optionallysubstituted C₂-C₆alkynyl; R⁸ is selected from the group consisting ofhydrogen, optionally substituted C₁-C₆alkyl, optionally substitutedC₃-C₈cycloalkyl, optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted heteroaryl, optionallysubstituted C₂-C₉heterocycloalkyl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); R⁹ and R¹⁰ together with the carbon atomsto which they are attached, form an optionally substituted nitrogencontaining 6-membered heteroaryl ring; R²⁵ and R²⁶ are eachindependently selected from the group consisting of hydrogen, optionallysubstituted C₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl,optionally substituted aryl, optionally substituted—(C₁-C₂alkylene)-(aryl), optionally substituted C₂-C₉heterocycloalkyl,optionally substituted heteroaryl, and optionally substituted—(C₁-C₂alkylene)-(heteroaryl); R²⁷ and R²⁸ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, optionallysubstituted aryl, optionally substituted —(C₁-C₂alkylene)-(aryl),optionally substituted C₂-C₉heterocycloalkyl, optionally substitutedheteroaryl, and optionally substituted —(C₁-C₂alkylene)-(heteroaryl); orR²⁷ and R²⁸ together with the nitrogen atom to which they are attached,form an optionally substituted C₂-C₉heterocycloalkyl ring; R³⁰ ishalogen,

each R³¹ is independently halogen, —OH, —CN, —NO₂, —NH₂, optionallysubstituted C₁-C₆alkyl, optionally substituted C₁-C₆alkoxy, optionallysubstituted C₁-C₆alkylamine, optionally substituted C₃-C₈cycloalkyl,optionally substituted C₂-C₉heterocycloalkyl, aryl, or heteroaryl; eachR³² and R³³ are each independently selected from the group consisting ofhydrogen, halogen, and C₁-C₆alkyl; R³⁴ and R³⁵ are each independentlyselected from the group consisting of hydrogen, optionally substitutedC₁-C₆alkyl, optionally substituted C₃-C₈cycloalkyl, and optionallysubstituted C₂-C₉heterocycloalkyl; or R³⁴ and R³⁵ together with thenitrogen atom to which they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring or an optionally substituted heteroaryl ring;p is 0, 1, 2, 3, or 4; r is 0, 1, 2, 3, or 4; and t is 2, 3, or 4; or apharmaceutically acceptable salt, stereoisomer, or solvate thereof. 19.The method of claim 16, wherein the FXR modulator is a compound ofFormula (VIIId), or a pharmaceutically acceptable salt, stereoisomer, orsolvate thereof:

wherein: each R¹¹ is independently selected from the group consisting ofhalogen, —CN, amino, alkylamino, C₁-C₆alkyl, C₁-C₆haloalkyl,C₁-C₆alkoxy, C₁-C₆haloalkoxy, C₃-C₈cycloalkyl, C₂-C₉heterocycloalkyl,aryl, heteroaryl, —C(O)OR¹², —C(O)N(R¹³)R¹⁴; each R¹² is independentlyselected from the group consisting of hydrogen and C₁-C₆alkyl; each R¹³and R¹⁴ are each independently selected from the group consisting ofhydrogen and C₁-C₆alkyl; or R¹³ and R¹⁴ together with the nitrogen atomto which they are attached, form an optionally substitutedC₂-C₉heterocycloalkyl ring; and n is 0, 1, 2, or
 3. 20. The method ofclaim 16, wherein the FXR modulator is a compound having the structure:

or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.21. (canceled)
 22. The method of claim 16, wherein the second agent isan CCR2/CCR5 antagonist selected from the group consisting ofcenicriviroc (CVC), vicriviroc, maraviroc and cochilioquinone A.
 23. Themethod of claim 16, wherein the second agent is an ASK1 inhibitorselected from GS-4997 (selonsertib)(5-(4-cyclopropyl-1H-imidazol-1-yl)-2-fluoro-N-(6-(4-isopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-4-methylbenzamide),NQDI-1 (ethyl2,7-dioxo-3,7-dihydro-2H-naphtho[1,2,3-de]quinoline-1-carboxylate),ML365 (2-methoxy-N-[3-[(3-methylbenzoyl)amino]phenyl]benzamide), MSC2032964A(N-[5-(cyclopropylamino)-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-pyridinecarboxamide) and TC ASK 10(4-(1,1-dimethylethyl)-N-[6-(1H-imidazol-1-yl)imidazo[1,2-a]pyridin-2-yl]benzamidedihydrochloride).
 24. The method of claim 16, wherein the second agentis a DPP-IV inhibitor selected from sitagliptin, saxagliptin,linagliptin, alogliptin, vildagliptin, gemigliptin, anagliptin,teneligliptin, trelagliptin, dutogliptin and omarigliptin.
 25. Themethod of claim 16, wherein the second agent is an SGLT2 inhibitorselected from canagliflozin, empagliflozin, dapagliflozin,ipragliflozin, tofogliflozin, sergliflozin etabonate, remogliflozinetabonate and ertugliflozin.
 26. The method of claim 16, wherein thesecond agent is a caspase protease inhibitor selected from the groupconsisting of emricasan, Q-VD-Oph, DEVD-CHO, zVAD-FMK, Pralnacasan andM867.
 27. The method of claim 16, wherein the second agent is a GLP-1agonist selected from exenatide, liraglutide, lixisenatide, albiglutide,dulaglutide, taspoglutide and semaglutide. 28.-38. (canceled)